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Qian L, Zhang S, Lin C, Lin J, Li Z. Depression exacerbates myocardial ischemia-reperfusion injury in mice via CNR2 gene and MIF-AMPK signaling pathway. Int J Cardiol 2024; 416:132505. [PMID: 39222886 DOI: 10.1016/j.ijcard.2024.132505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 08/20/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Myocardial ischemia-reperfusion(I/R)injury constitute the fundamental pathophysiology of acute myocardial infarction (AMI). Ischemic heart releases macrophage migration inhibitory factor (MIF), which activates MIF- AMPK signaling pathway. Depression is a significant risk factor for AMI. In a state of depression, peripheral expression of cannabinoid receptor 2 (CNR2) genes was downregulated. AIMS We investigated the mechanism by which depression exacerbates myocardial I/R injury through the CNR2 and MIF-AMPK signaling pathways. METHODS We established mouse models of depression and myocardial I/R. Left ventricular function was assessed using cardiac ultrasound and TTC staining. The protein levels of myocardial CNR2, MIF, AMPK, and ACC were determined by Western blot, while the expression level of CNR2 was measured using RT-qPCR. Additionally, MIF content in peripheral blood was quantified using ELISA. RESULTS After I/R, the expression level of CNR2 was found to be lower in the depression group, leading to a deterioration in left heart function. Depressed mice exhibited lower secretion of MIF, accompanied by a decrease in the activation of the MIF-AMPK signaling pathway. However, injection of CNR2 agonist JWH133 prior to ischemia increased the activation of the MIF-AMPK signaling pathway, while CNR2 inhibitor AM630 decreased the activation. LIMITATIONS Further research is needed to investigate the specific neuroendocrine mechanism affecting myocardial CNR2 expression in depression. And these experimental conclusions require further verification at the cellular level. CONCLUSIONS The activation of CNR2 in myocardium following I/R is impeded by depression, thereby exacerbating myocardial I/R injury through attenuation of the MIF-AMPK signaling pathway activation.
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Affiliation(s)
- Lu Qian
- Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Suqin Zhang
- Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Cong Lin
- Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Jiafeng Lin
- Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
| | - Zhuoyuan Li
- Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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Christopoulou ME, Aletras AJ, Papakonstantinou E, Stolz D, Skandalis SS. WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD. Int J Mol Sci 2024; 25:10049. [PMID: 39337534 PMCID: PMC11432718 DOI: 10.3390/ijms251810049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1-MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes.
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Affiliation(s)
- Maria-Elpida Christopoulou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Alexios J Aletras
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
| | - Eleni Papakonstantinou
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Daiana Stolz
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
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Jahanbani F, Sing JC, Maynard RD, Jahanbani S, Dafoe J, Dafoe W, Jones N, Wallace KJ, Rastan A, Maecker HT, Röst HL, Snyder MP, Davis RW. Longitudinal cytokine and multi-modal health data of an extremely severe ME/CFS patient with HSD reveals insights into immunopathology, and disease severity. Front Immunol 2024; 15:1369295. [PMID: 38650940 PMCID: PMC11033372 DOI: 10.3389/fimmu.2024.1369295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 03/18/2024] [Indexed: 04/25/2024] Open
Abstract
Introduction Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health,textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies. Methods This study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention. Results Longitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression. Discussion Our study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice.
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Affiliation(s)
- Fereshteh Jahanbani
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Justin Cyril Sing
- Department of Molecular Genetics, Donnelly Center, University of Toronto, Toronto, ON, Canada
| | - Rajan Douglas Maynard
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Shaghayegh Jahanbani
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Veterans Affairs (VA) Palo Alto Health Care System, Palo Alto, CA, United States
| | - Janet Dafoe
- ME/CFS Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Whitney Dafoe
- ME/CFS Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Nathan Jones
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Kelvin J. Wallace
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Azuravesta Rastan
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Holden T. Maecker
- Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Pulmonary and Critical Care Medicine, Institute of Immunity, Transplantation, and Infectious Diseases, Stanford University, Palo Alto, CA, United States
| | - Hannes L. Röst
- Department of Molecular Genetics, Donnelly Center, University of Toronto, Toronto, ON, Canada
| | - Michael P. Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Ronald W. Davis
- ME/CFS Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine, Palo Alto, CA, United States
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Katsarou EI, Reid N, Lianou DT, Fthenakis GC. Stress related to wild canid predators near dairy sheep farms associated with increased somatic cell counts in bulk-tank milk. Sci Rep 2024; 14:3252. [PMID: 38331991 PMCID: PMC10853181 DOI: 10.1038/s41598-024-53887-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/06/2024] [Indexed: 02/10/2024] Open
Abstract
We investigated the association between wild canid predators reported near sheep farms throughout Greece and somatic cell counts in bulk-tank milk as a reflection of milk quality. The study included 325 dairy sheep flocks, where bulk-tank milk somatic cell counts and total bacterial counts were measured and staphylococci were isolated. Farms were divided into three groups: Cohort A (farms with no reports of wild canid predators nearby), B (farms with canid predators (golden jackal and grey wolf) nearby yet with no experience of livestock losses to predation) and C (farms with canid predators nearby and livestock losses to predation). Somatic cell counts in bulk-tank milk of Cohort C farms were significantly higher, + 43% and + 29%, compared to those for Cohorts A and B, respectively: 0.617 × 106 cells mL-1 versus 0.433 × 106 or 0.477 × 106 cells mL-1, respectively. The presence of wild canid predators near sheep farms was associated with lower quality milk potentially indicative of stress consistent with the potential effects of a landscape of fear. Increasing biosecurity measures at livestock farms, e.g., fencing, and presence of livestock guard dogs could minimise predation risk, whilst also improving livestock welfare by reducing predator-associated stress.
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Affiliation(s)
- Eleni I Katsarou
- Veterinary Faculty, University of Thessaly, 43100, Karditsa, Greece
| | - Neil Reid
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK
| | - Daphne T Lianou
- Veterinary Faculty, University of Thessaly, 43100, Karditsa, Greece
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Talreja J, Peng C, Samavati L. MIF modulates p38/ERK phosphorylation via MKP-1 induction in sarcoidosis. iScience 2024; 27:108746. [PMID: 38299032 PMCID: PMC10829885 DOI: 10.1016/j.isci.2023.108746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 09/21/2023] [Accepted: 12/12/2023] [Indexed: 02/02/2024] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a versatile cytokine that influences a variety of cellular processes important for immune regulation and tissue homeostasis. Sarcoidosis is a granulomatous disease characterized by extensive local inflammation and increased T helper cell mediated cytokines. We have shown that MIF has a modulatory role in cytokine networks in sarcoidosis. We investigated the effect of exogenous MIF on sarcoidosis alveolar macrophages (AMs), CD14+ monocytes and peripheral blood mononuclear cells (PBMCs). Our results showed that MIF negatively regulates the increased MAPKs (pp38 and pERK1/2) activation by inducing Mitogen-activated protein kinase phosphatase (MKP)-1. We found that MIF decreased IL-6 and IL-1β production, increased the percentage of regulatory T-cells (Tregs), and induced IL-1R antagonist (IL-1RA) and IL-10 production. Thus, the results of our study suggest that exogenous MIF modulates MAPK activation by inducing MKP-1and Tregs as well as IL-10 and IL-1RA, and hence plays a modulatory role in immune activation in sarcoidosis.
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Affiliation(s)
- Jaya Talreja
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University, School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA
| | - Changya Peng
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University, School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA
| | - Lobelia Samavati
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University, School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA
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Jia Q, Hao RJL, Lu XJ, Sun SQ, Shao JJ, Su X, Huang QF. Identification of hub biomarkers and immune cell infiltration characteristics of polymyositis by bioinformatics analysis. Front Immunol 2022; 13:1002500. [PMID: 36225941 PMCID: PMC9548705 DOI: 10.3389/fimmu.2022.1002500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/09/2022] [Indexed: 11/13/2022] Open
Abstract
Background Polymyositis (PM) is an acquirable muscle disease with proximal muscle involvement of the extremities as the main manifestation; it is a category of idiopathic inflammatory myopathy. This study aimed to identify the key biomarkers of PM, while elucidating PM-associated immune cell infiltration and immune-related pathways. Methods The gene microarray data related to PM were downloaded from the Gene Expression Omnibus database. The analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were performed on differentially expressed genes (DEGs). The hub genes of PM were identified using weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) algorithm, and the diagnostic accuracy of hub markers for PM was assessed using the receiver operating characteristic curve. In addition, the level of infiltration of 28 immune cells in PM and their interrelationship with hub genes were analyzed using single-sample GSEA. Results A total of 420 DEGs were identified. The biological functions and signaling pathways closely associated with PM were inflammatory and immune processes. A series of four expression modules were obtained by WGCNA analysis, with the turquoise module having the highest correlation with PM; 196 crossover genes were obtained by combining DEGs. Subsequently, six hub genes were finally identified as the potential biomarkers of PM using LASSO algorithm and validation set verification analysis. In the immune cell infiltration analysis, the infiltration of T lymphocytes and subpopulations, dendritic cells, macrophages, and natural killer cells was more significant in the PM. Conclusion We identified the hub genes closely related to PM using WGCNA combined with LASSO algorithm, which helped clarify the molecular mechanism of PM development and might have great significance for finding new immunotherapeutic targets, and disease prevention and treatment.
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Affiliation(s)
- Qi Jia
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Rui-Jin-Lin Hao
- Medical School of Nantong University, Nantong, China
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiao-Jian Lu
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Shu-Qing Sun
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Jun-Jie Shao
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xing Su
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- *Correspondence: Qing-Feng Huang, ; Xing Su,
| | - Qing-Feng Huang
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
- *Correspondence: Qing-Feng Huang, ; Xing Su,
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Khalil RM, Alaa S, Eissa H, Youssef I. Early Prediction of a Pre-Symptomatic Neurodegeneration Disorder by Measuring Macrophage Inhibitory Factor Level in Diabetic Patients. J Alzheimers Dis 2022; 88:1167-1177. [PMID: 35754265 DOI: 10.3233/jad-215561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The relationship between diabetes mellitus and neurodegenerative disorders has been of great interest. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine in which a variety of signaling cascades are activated through it. MIF has been involved in the pathogenesis of several diseases and can predict early pre-symptomatic stages of neurodegeneration in diabetic patients. OBJECTIVE To investigate whether serum MIF could predict brain neurodegeneration at the early pre-symptomatic stages in diabetic patients. METHODS We examined adults with type 2 diabetes mellitus and compared with normal control adults using a short form of the IQCODE and biochemical examination, including assessment of HA1C, fasting blood glucose, lipid profile, and MIF which was measured by ELISA technique. Correlations between parameters were studied. Computational PathLinker bioinformatic tool was used to search for potential pathway reconstructions for the insulin/amyloid-β/MIF signaling. RESULTS We demonstrated that MIF level was increased in the serum at the early pre-symptomatic stages of neurodegenerative disorder in diabetic patients. In addition, network analysis demonstrates that insulin receptor substrate 1 can ameliorate amyloid-β protein precursor through COP9 signalosome complex subunit 5 that enhances MIF elevation. CONCLUSION Diagnosis processes could not be used as routine examinations for still pre-symptomatic neurodegenerative disorders. This may be due to the time constraints and the heavy dependence on the physician's experience. Therefore, serum MIF level could predict brain neurodegeneration at the early pre-symptomatic stages in diabetic patients which may support its potential utility as a clinically useful biomarker.
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Affiliation(s)
- Rania M Khalil
- Biochemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Shereen Alaa
- Pharmacology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hanan Eissa
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Ndreu L, Sasse S, Karlberg AT, Karlsson I. Haptenation of Macrophage Migration Inhibitory Factor: A Potential Biomarker for Contact Hypersensitivity. FRONTIERS IN TOXICOLOGY 2022; 4:856614. [PMID: 35465102 PMCID: PMC9019732 DOI: 10.3389/ftox.2022.856614] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Abstract
The immunological response in contact hypersensitivity is incited by small electrophilic compounds, known as haptens, that react with endogenous proteins after skin absorption. However, the identity of hapten-modified proteins seen as immunogenic remains as yet largely unknown. In a recent study, we have for the first time identified a hapten-modified protein in the local lymph nodes of mice treated topically with the model hapten tetramethylrhodamine isothiocyanate (TRITC). The TRITC modification was located on the N-terminal proline of the protein macrophage migration inhibitory factor (MIF). The focus of the current study was to investigate the presence of the same hapten-protein conjugate in blood samples from mice treated topically with TRITC. Furthermore, TRITC modifications of the two major blood proteins, namely hemoglobin (Hb) and albumin (Alb), as well as TRITC modifications of MIF other than the N-terminal proline, were examined. Following incubation with different molar ratios of TRITC, a proteomic approach was applied to characterize conjugate formation of the three aforementioned proteins, using high resolution mass spectrometry (HRMS). The targeted screening of the TRITC-treated mice blood and lymph node samples for these sites led to the identification of only the same TRITC-MIF conjugate previously detected in the lymph nodes. No Hb and Alb conjugates were detected. Quantification of both the TRITC-modified and unmodified N-terminal peptide of MIF in blood and lymph node samples gave interesting insights of MIF’s role in murine contact hypersensitivity. Incubation of MIF with four different haptens encompassing different reactivity mechanisms and potencies, showed adduct formation at different amino acid residues, suggesting that MIF can be the preferred target for a wide variety of haptens. The present study provides essential progress toward understanding of hapten-protein conjugate formation in contact hypersensitivity and identifies hapten-modified MIF as a potential biomarker for this condition. Further investigation of MIF as a target protein can be a next step to determine if MIF is a biomarker that can be used to develop better diagnostic tools and targeted therapeutics for individuals with allergic contact dermatitis.
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Affiliation(s)
- Lorena Ndreu
- Department of Environmental Science, Stockholm University, Stockholm, Sweden
| | - Samantha Sasse
- Department of Environmental Science, Stockholm University, Stockholm, Sweden
| | - Ann-Therese Karlberg
- Department of Chemistry and Molecular Biology, Dermatochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Isabella Karlsson
- Department of Environmental Science, Stockholm University, Stockholm, Sweden
- *Correspondence: Isabella Karlsson,
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Wagner AD, Wittkop U, Thalmann J, Willmen T, Gödecke V, Hodam J, Ronicke S, Zenke M. Glucocorticoid Effects on Tissue Residing Immune Cells in Giant Cell Arteritis: Importance of GM-CSF. Front Med (Lausanne) 2021; 8:709404. [PMID: 34557501 PMCID: PMC8452956 DOI: 10.3389/fmed.2021.709404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/17/2021] [Indexed: 11/13/2022] Open
Abstract
Giant cell arteritis (GCA) is a systemic granulomatous vasculitis clinically characterized by a prompt response to glucocorticoid therapy. Dendritic cells (DCs) play a central role in the pathogenesis of the disease and are increased in temporal arteries from GCA patients. The aim of this study was to determine the effects of glucocorticoid therapy on granulomatous infiltrates and on peripheral DCs of GCA patients. Immunohistochemical staining of temporal artery specimens from 41 GCA patients revealed a rapid reduction of the number of DCs after initiation of glucocorticoid treatment. TUNEL staining was performed to quantify apoptotic S100+ DC, CD3+ T cells, and CD68+ macrophages in the granulomatous infiltrates. An increase of apoptotic cells up to 9 ± 2% after 4–5 days of glucocorticoid therapy and up to 27 ± 5% (p < 0.001, compared to earlier timepoints) after 6–10 days was detected. A decrease of CCL19 and CCL21 expression was observed after starting glucocorticoid therapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also significantly decreased under glucocorticoid therapy. No GM-CSF expression was detected in the control specimens. Glucocorticoid therapy leads to a rapid, time-dependent reduction of DCs in temporal arteries from GCA patients and reduction of mediators for cell migration. Our data suggest GM-CSF as a novel therapeutic target of GCA.
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Affiliation(s)
- Annette D Wagner
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Ulrike Wittkop
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Jessica Thalmann
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Tina Willmen
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Vega Gödecke
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Justyna Hodam
- Deutsches Rotes Kreuz (DRK) Clinic for Child and Adolescent Psychiatry, Bad Neuenahr, Germany
| | - Simon Ronicke
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Martin Zenke
- Department of Cell Biology, Institute for Biomedical Engineering, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) Aachen University Medical School, Aachen, Germany.,Helmholtz Institute for Biomedical Engineering, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) Aachen University, Aachen, Germany
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Yao J, Leng L, Fu W, Li J, Bronner C, Bucala R. ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus. Arthritis Rheumatol 2021; 73:1931-1942. [PMID: 33844457 DOI: 10.1002/art.41753] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/25/2021] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Macrophage migration inhibitory factor (MIF) is an inflammatory and neurorendocrine mediator that counterregulates glucocorticoid immunosuppression. MIF polymorphisms, which comprise a variant promoter microsatellite (-794 CATT5-8 ), are linked genetically to autoimmune disease severity and to glucocorticoid resistance. While invasive stimuli increase MIF expression, MIF also is up-regulated by glucocorticoids, which serve as a physiologic regulator of inflammatory responses. This study was undertaken to define interactions between the MIF promoter, the glucocorticoid receptor (GR), and the transcription factor inverted CCAAT box binding protein 90 kd (ICBP90) (also referred to as UHRF1), which binds to the promoter in a -794 CATT5-8 length-dependent manner, to regulate MIF transcription. METHODS Interactions of ICBP90, GR, and activator protein 1 (AP-1) with MIF -794 CATT5-8 promoter constructs were assessed by coimmunoprecipitation, Western blotting, and genetic knockdown. Nuclear colocalization studies were performed using anti-transcription factor antibodies and confocal microscopy of glucocorticoid-treated cells. MIF transcription was studied in CEM-C7 T cells, and the impact of the MIF -794 CATT5-8 microsatellite variation confirmed in peripheral blood T cells and in rheumatoid synovial fibroblasts of defined MIF genotype. Functional interactions were quantified by apoptosis and apoptotic signaling in high- and low-genotypic MIF-expressing human cells. RESULTS We defined functional interactions between the transcription factors ICBP90, the GR, and AP-1 that up-regulated MIF transcription in a -794 CATT5-8 length-dependent manner. Experimental reduction of ICBP90, GR, or AP-1 decreased MIF expression and increased glucocorticoid sensitivity, leading to enhanced apoptosis in T lymphocytes and in rheumatoid synovial fibroblasts. CONCLUSION These findings suggest a mechanism for genetic variation of glucocorticoid-regulated MIF transcription, with implications for autoimmune disease severity and glucocorticoid responsiveness.
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Affiliation(s)
- Jie Yao
- Shunde Hospital, Southern Medical University, Foshan, China
| | - Lin Leng
- Yale University School of Medicine, New Haven, Connecticut
| | - Weiling Fu
- Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jia Li
- Yale University School of Medicine, New Haven, Connecticut
| | - Christian Bronner
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Ligue Nationale Contre le Cancer Equipe Labellisée Illkirch, Alsace, France
| | - Richard Bucala
- Yale University School of Medicine, New Haven, Connecticut
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Arthritis and the role of endogenous glucocorticoids. Bone Res 2020; 8:33. [PMID: 32963891 PMCID: PMC7478967 DOI: 10.1038/s41413-020-00112-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 07/09/2020] [Accepted: 07/27/2020] [Indexed: 12/17/2022] Open
Abstract
Rheumatoid arthritis and osteoarthritis, the most common forms of arthritis, are chronic, painful, and disabling conditions. Although both diseases differ in etiology, they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage, bone, and synovium. While the potent anti-inflammatory properties of therapeutic (i.e., exogenous) glucocorticoids have been heavily researched and are widely used in clinical practice, the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood. Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis. Furthermore, these models indicate that endogenous glucocorticoid signaling in macrophages, mast cells, and chondrocytes has anti-inflammatory effects, while signaling in fibroblast-like synoviocytes, myocytes, osteoblasts, and osteocytes has pro-inflammatory actions in rheumatoid arthritis. Conversely, in osteoarthritis, endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions. Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.
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Hada N, Kuramochi M, Izawa T, Kuwamura M, Yamate J. Effects of dexamethasone on hepatic macrophages in normal livers and thioacetamide-induced acute liver lesions in rats. J Toxicol Pathol 2020; 33:237-246. [PMID: 33239842 PMCID: PMC7677630 DOI: 10.1293/tox.2020-0016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/07/2020] [Indexed: 12/27/2022] Open
Abstract
Resident and infiltrative macrophages play important roles in the development of
pathological lesions. M1/M2 macrophage polarization with respective CD68 and CD163
expression remains unclear in chemically induced liver injury. This study was aimed at
investigating the influence of macrophages on normal and chemically induced liver injury.
For this, dexamethasone (DX), an immunosuppressive drug, was administered in normal rats
and thioacetamide (TAA)-treated rats. Liver samples were collected and analyzed with
immunohistochemical methods. Repeated injections of DX (0.5 or 1.0 mg/kg BW) for 3, 7 and
11 days reduced the number of CD163 positive hepatic resident macrophages (Kupffer cells)
in normal livers, while increasing AST and ALT levels. In TAA (300 mg/kg BW)-treated rats
injected with DX (0.5 mg/kg BW) pretreatment, the number of M1 and M2 macrophages showed a
significant decrease compared with that of TAA-treated rats without DX treatment.
Additionally, reparative fibrosis resulting from hepatocyte injury induced by TAA
injection was suppressed by DX pretreatment. Our data suggested that macrophages could
influence not only normal hepatic homeostasis (reflected by AST and ALT levels) but also
chemically induced hepatic lesion development (reduced reparative fibrosis).
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Affiliation(s)
- Noa Hada
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Mizuki Kuramochi
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Takeshi Izawa
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Mitsuru Kuwamura
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
| | - Jyoji Yamate
- Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan
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Pinto P, da Silva MB, Moreira FC, Bouth RC, Gobbo AR, Sandoval TV, Ribeiro-Dos-Santos AM, Vidal AF, Barreto JG, Santos S, Spencer JS, Salgado CG, Ribeiro-Dos-Santos Â. Leprosy piRnome: exploring new possibilities for an old disease. Sci Rep 2020; 10:12648. [PMID: 32724108 PMCID: PMC7387468 DOI: 10.1038/s41598-020-69355-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 07/03/2020] [Indexed: 12/19/2022] Open
Abstract
Leprosy, which is caused by the human pathogen Mycobacterium leprae, causes nerve damage, deformity and disability in over 200,000 people every year. Because of the long doubling time of M. leprae (13 days) and the delayed onset of detectable symptoms, which is estimated to be approximately 3-7 years after infection, there is always a large percentage of subclinically infected individuals in the population who will eventually develop the disease, mainly in endemic countries. piRNAs comprise the largest group of small noncoding RNAs found in humans, and they are distinct from microRNAs (miRNAs) and small interfering RNAs (siRNAs). piRNAs function in transposon silencing, epigenetic regulation, and germline development. The functional role of piRNAs and their associated PIWI proteins have started to emerge in the development of human cancers and viral infections, but their relevance to bacterial diseases has not been investigated. The present study reports the piRNome of human skin, revealing that all but one of the piRNAs examined are downregulated in leprosy skin lesions. Considering that one of the best characterized functions of piRNAs in humans is posttranscriptional mRNA silencing, their functions are similar to what we have described for miRNAs, including acting on apoptosis, M. leprae recognition and engulfment, Schwann cell (SC) demyelination, epithelial-mesenchymal transition (EMT), loss of sensation and neuropathic pain. In addition to new findings on leprosy physiopathology, the discovery of relevant piRNAs involved in disease processes in human skin may provide new clues for therapeutic targets, specifically to control nerve damage, a prominent feature of leprosy that has no currently available pharmaceutical treatment.
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Affiliation(s)
- Pablo Pinto
- Human and Medical Genetics Laboratory, Institute of Biological Sciences (ICB), UFPA, Belém, 66075110, Brazil
- Oncology Research Center (NPO), UFPA, Belém, 66075110, Brazil
| | - Moisés Batista da Silva
- Dermato-Immunology Laboratory, Institute of Biological Sciences (ICB), UFPA, Marituba, 67200000, Brazil
| | | | - Raquel Carvalho Bouth
- Dermato-Immunology Laboratory, Institute of Biological Sciences (ICB), UFPA, Marituba, 67200000, Brazil
| | - Angélica Rita Gobbo
- Dermato-Immunology Laboratory, Institute of Biological Sciences (ICB), UFPA, Marituba, 67200000, Brazil
| | - Tatiana Vinasco Sandoval
- Human and Medical Genetics Laboratory, Institute of Biological Sciences (ICB), UFPA, Belém, 66075110, Brazil
| | | | - Amanda Ferreira Vidal
- Human and Medical Genetics Laboratory, Institute of Biological Sciences (ICB), UFPA, Belém, 66075110, Brazil
| | | | - Sidney Santos
- Human and Medical Genetics Laboratory, Institute of Biological Sciences (ICB), UFPA, Belém, 66075110, Brazil
- Oncology Research Center (NPO), UFPA, Belém, 66075110, Brazil
| | - John Stewart Spencer
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, 80523-1601, USA
| | - Claudio Guedes Salgado
- Dermato-Immunology Laboratory, Institute of Biological Sciences (ICB), UFPA, Marituba, 67200000, Brazil.
| | - Ândrea Ribeiro-Dos-Santos
- Human and Medical Genetics Laboratory, Institute of Biological Sciences (ICB), UFPA, Belém, 66075110, Brazil.
- Oncology Research Center (NPO), UFPA, Belém, 66075110, Brazil.
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The Role of Macrophage Migration Inhibitory Factor in Alzheimer's Disease: Conventionally Pathogenetic or Unconventionally Protective? Molecules 2020; 25:molecules25020291. [PMID: 31936865 PMCID: PMC7024279 DOI: 10.3390/molecules25020291] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/03/2020] [Accepted: 01/09/2020] [Indexed: 02/06/2023] Open
Abstract
Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer′s disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.
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15
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Stoppe C, Averdunk L, Goetzenich A, Soppert J, Marlier A, Kraemer S, Vieten J, Coburn M, Kowark A, Kim BS, Marx G, Rex S, Ochi A, Leng L, Moeckel G, Linkermann A, El Bounkari O, Zarbock A, Bernhagen J, Djudjaj S, Bucala R, Boor P. The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery. Sci Transl Med 2019; 10:10/441/eaan4886. [PMID: 29769287 DOI: 10.1126/scitranslmed.aan4886] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 12/22/2017] [Accepted: 04/13/2018] [Indexed: 12/20/2022]
Abstract
Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; P = 0.03). Experimental AKI was induced in wild-type and Mif-/- mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. Mif-deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.
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Affiliation(s)
- Christian Stoppe
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
| | - Luisa Averdunk
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
| | - Andreas Goetzenich
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen, Aachen, Germany
| | - Josefin Soppert
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.,Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen, Aachen, Germany
| | - Arnaud Marlier
- Department of Nephrology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Sandra Kraemer
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen, Aachen, Germany
| | - Jil Vieten
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
| | - Mark Coburn
- Department of Anesthesiology, University Hospital, RWTH Aachen, Aachen, Germany
| | - Ana Kowark
- Department of Anesthesiology, University Hospital, RWTH Aachen, Aachen, Germany
| | - Bong-Song Kim
- Department of Plastic and Reconstructive Surgery, Hand Surgery, Burn Center, RWTH Aachen, Aachen, Germany
| | - Gernot Marx
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
| | - Steffen Rex
- Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium
| | - Akinobu Ochi
- Department of Nephropathology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Lin Leng
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Gilbert Moeckel
- Department of Nephropathology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Omar El Bounkari
- Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Alexander Zarbock
- Department of Anesthesiology, Critical Care Medicine and Pain Therapy, University Hospital Münster, Münster, Germany
| | - Jürgen Bernhagen
- Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany. .,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.,Munich Cluster for Systems Neurology (EXC 1010 SyNergy), Munich, Germany
| | - Sonja Djudjaj
- Institute of Pathology and Department of Nephrology, University Hospital, RWTH Aachen, Aachen, Germany
| | - Richard Bucala
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Peter Boor
- Institute of Pathology and Department of Nephrology, University Hospital, RWTH Aachen, Aachen, Germany. .,Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia
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16
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Kang I, Bucala R. The immunobiology of MIF: function, genetics and prospects for precision medicine. Nat Rev Rheumatol 2019; 15:427-437. [DOI: 10.1038/s41584-019-0238-2] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2019] [Indexed: 01/01/2023]
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17
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Barden A, Phillips M, Hill LM, Fletcher EM, Mas E, Loh PS, French MA, Ho KM, Mori TA, Corcoran TB. Antiemetic doses of dexamethasone and their effects on immune cell populations and plasma mediators of inflammation resolution in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids 2018; 139:31-39. [PMID: 30471772 DOI: 10.1016/j.plefa.2018.11.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/07/2018] [Accepted: 11/07/2018] [Indexed: 01/04/2023]
Abstract
INTRODUCTION The synthetic glucocorticoid dexamethasone is a commonly administered antiemetic. It has immunosuppressive effects and may alter postoperative blood glucose concentrations. Dexamethasone can effect key enzymes involved in inflammation resolution that is an active process driven by specialised lipid mediators of inflammation resolution (SPM). The purpose of this study in healthy volunteers was to examine whether dexamethasone effects cell populations and synthesis of SPM that are critical for the resolution of inflammation. METHODS Thirty-two healthy volunteers were randomly allocated to receive saline (Control) or dexamethasone 2 mg, 4 mg or 8 mg intravenously. Venous blood samples were collected at baseline before administration of treatment, and at 4 h, 24 h and one-week post-treatment. At each time point, measurements included blood glucose and macrophage migration inhibition factor (MMIF), full blood count including lymphocyte subsets, monocytes, neutrophils, eosinophils and basophils by flow cytometry, and plasma SPM using liquid chromatography tandem mass spectrometry. The effect of dexamethasone dose and time on all measures was analysed using linear mixed models. RESULTS There was a dose-dependent increase in neutrophil count after dexamethasone that persisted for 24 h. In contrast, there was a dose-dependent reduction in counts of monocytes, lymphocytes, basophils and eosinophils 4 h after dexamethasone, followed by a rebound increase in cell counts at 24 h. Seven days after administration of dexamethasone, all cell counts were similar to baseline levels. MMIF concentration, glucose and natural killer cell counts were not significantly affected by dexamethasone. There was a significant gender effect on plasma SPM such that levels of 17-HDHA, RvD1, 17R-RvD1 and RvE2 in females were on average 14%-50% lower than males. In a linear mixed model that adjusted for neutrophil count, there was a significant interaction between the dose of dexamethasone and time, on plasma 17R-RvD1 such that plasma 17R-RvD1 fell in a dose-dependent manner until 4 h after administration of dexamethasone. There were no significant effects of dexamethasone on the other plasma SPM (18-HEPE, RvE2, 17-HDHA, RvD1, RvD2 and 14-HDHA) measured. DISCUSSION This is the first study in healthy volunteers to demonstrate that commonly employed antiemetic doses of dexamethasone affect immune cell populations and plasma levels of 17R-RvD1 an SPM with anti-nociceptive properties. If similar changes occur in surgical patients, then this may have implications for acute infection risk in the post-operative period.
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Affiliation(s)
- Anne Barden
- Medical School, Royal Perth Hospital Unit, University of Western Australia, Box X2214 GPO Perth, Western Australia 6847, Australia.
| | - Michael Phillips
- Harry Perkins Institute for Medical Research, University of Western Australia, Australia
| | - Lisa M Hill
- Department of Anaesthesia, St John of God Midland and Mount Lawley Hospitals, Perth, Western Australia, Australia
| | - Evelyn M Fletcher
- Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Australia
| | - Emilie Mas
- Medical School, Royal Perth Hospital Unit, University of Western Australia, Box X2214 GPO Perth, Western Australia 6847, Australia
| | - P S Loh
- Department of Anaesthesiology and Intensive Care, University of Malaya, Malaysia
| | - Martyn A French
- UWA Medical School and School of Biomedical Sciences, University of Western Australia, Perth, Australia; Department of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Australia
| | - Kwok M Ho
- Department of Intensive Care Medicine, Royal Perth Hospital, Australia; School of Population Health, University of Western Australia, Australia
| | - Trevor A Mori
- Medical School, Royal Perth Hospital Unit, University of Western Australia, Box X2214 GPO Perth, Western Australia 6847, Australia
| | - Tomás B Corcoran
- Medical School, Royal Perth Hospital Unit, University of Western Australia, Box X2214 GPO Perth, Western Australia 6847, Australia; Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Australia
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18
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Cui D, Peng Y, Zhang C, Li Z, Su Y, Qi Y, Xing M, Li J, Kim GE, Su KN, Xu J, Wang M, Ding W, Piecychna M, Leng L, Hirasawa M, Jiang K, Young L, Xu Y, Qi D, Bucala R. Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy. J Clin Invest 2018; 128:4997-5007. [PMID: 30295645 PMCID: PMC6205380 DOI: 10.1172/jci93090] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 08/28/2018] [Indexed: 12/14/2022] Open
Abstract
Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.
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Affiliation(s)
- Donghong Cui
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
- Brain Science and Technology Research Center, Shanghai Jiao Tong University, China
| | - Yanmin Peng
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - Chengfang Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
- Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai, China
| | - Zezhi Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yousong Su
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yadan Qi
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Mengjuan Xing
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Jia Li
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Grace E. Kim
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kevin N. Su
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jinjie Xu
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Meiti Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Wenhua Ding
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Marta Piecychna
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lin Leng
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Michiru Hirasawa
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Kaida Jiang
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Lawrence Young
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yifeng Xu
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - Dake Qi
- Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Richard Bucala
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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19
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Lipschutz R, Bick J, Nguyen V, Lee M, Leng L, Grigorenko E, Bucala R, Mayes LC, Crowley MJ. Macrophage migration inhibitory factor (MIF) gene is associated with adolescents' cortisol reactivity and anxiety. Psychoneuroendocrinology 2018; 95:170-178. [PMID: 29870971 DOI: 10.1016/j.psyneuen.2018.05.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 05/23/2018] [Accepted: 05/24/2018] [Indexed: 12/19/2022]
Abstract
Emerging evidence points to interactions between inflammatory markers and stress reactivity in predicting mental health risk, but underlying mechanisms are not well understood. Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic cytokine involved in inflammatory signaling and Hypothalamus Pituitary Adrenal (HPA) axis stress-response, and has recently been identified as a candidate biomarker for depression and anxiety risk. We examined polymorphic variations of the MIF gene in association with baseline MIF levels, HPA axis reactivity, and self-reported anxiety responses to a social stressor in 74 adolescents, ages 10-14 years. Genotyping was performed for two polymorphisms, the -794 CATT5-8 tetranucleotide repeat and the -173*G/C single nucleotide polymorphism (SNP). Youth carrying the MIF-173*C and CATT7 alleles displayed attenuated cortisol reactivity when compared with non-carriers. Children with the CATT7-173*C haplotype displayed lower cortisol reactivity to the stressor compared to those without this haplotype. Additionally, the CATT5-173*C and CATT6-173*C haplotypes were associated with lower self-reported anxiety ratings across the stressor. Results extend prior work pointing to the influence of MIF signaling on neuroendocrine response to stress and suggest a potential pathophysiological pathway underlying risk for stress-related physical and mental health disorders. To our knowledge, these are the first data showing associations between the MIF gene, HPA axis reactivity, and anxiety symptoms during adolescence.
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Affiliation(s)
- Rebecca Lipschutz
- Department of Psychology, University of Houston, Houston, TX, United States
| | - Johanna Bick
- Department of Psychology, University of Houston, Houston, TX, United States.
| | - Victoria Nguyen
- Child Study Center, Yale School of Medicine, New Haven, CT, United States
| | - Maria Lee
- Child Study Center, Yale School of Medicine, New Haven, CT, United States
| | - Lin Leng
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT, United States
| | - Elena Grigorenko
- Department of Psychology, University of Houston, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Richard Bucala
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT, United States
| | - Linda C Mayes
- Child Study Center, Yale School of Medicine, New Haven, CT, United States
| | - Michael J Crowley
- Child Study Center, Yale School of Medicine, New Haven, CT, United States
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20
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Presti M, Mazzon E, Basile MS, Petralia MC, Bramanti A, Colletti G, Bramanti P, Nicoletti F, Fagone P. Overexpression of macrophage migration inhibitory factor and functionally-related genes, D-DT, CD74, CD44, CXCR2 and CXCR4, in glioblastoma. Oncol Lett 2018; 16:2881-2886. [PMID: 30127875 PMCID: PMC6096183 DOI: 10.3892/ol.2018.8990] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 04/26/2018] [Indexed: 01/02/2023] Open
Abstract
The macrophage migration inhibition factor (MIF) is a cytokine with multiple biological functions, including the cancer-associated processes, cell cycle deregulation, angiogenesis and metastatization. The present study investigated the expression of MIF and its functionally associated genes (D-DT, CD74, CD44, CXCR2 and CXCR4) in glioblastoma multiforme (GBM). The data were obtained from The Cancer Genome Atlas databank, through the cBioportal web-based utility (cbioportal.org/). A significant increase was observed in the majority of these genes in GBM samples compared with lower grade gliomas, however no significant correlation among the selected genes and the overall survival of the patients was identified. In contrast, the expression of MIF exhibited a trend toward an increase in overall survival and a significant increase of MIF expression was observed in samples of patients who underwent neoadjuvant treatment. In conclusion these data indicate that MIF and its receptors are involved in GBM progression and maintenance. Deciphering the precise biological significance in GBM would favor the adoption of tailored approaches to modulate the function of MIF and its associated genes for the treatment of the disease.
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Affiliation(s)
- Mario Presti
- Department of Biomedical and Biotechnological Sciences, Biological Tower, University of Catania, Catania I-95123, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi 'Bonino-Pulejo', Messina I-98124, Italy
| | - Maria Sofia Basile
- Department of Biomedical and Biotechnological Sciences, Biological Tower, University of Catania, Catania I-95123, Italy
| | - Maria Cristina Petralia
- Department of Biomedical and Biotechnological Sciences, Biological Tower, University of Catania, Catania I-95123, Italy.,Department of Formative Processes, University of Catania, Catania I-98124, Italy
| | | | - Giuseppe Colletti
- Department of Biomedical and Biotechnological Sciences, Biological Tower, University of Catania, Catania I-95123, Italy
| | | | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, Biological Tower, University of Catania, Catania I-95123, Italy
| | - Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, Biological Tower, University of Catania, Catania I-95123, Italy
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Fagone P, Mazzon E, Cavalli E, Bramanti A, Petralia MC, Mangano K, Al-Abed Y, Bramati P, Nicoletti F. Contribution of the macrophage migration inhibitory factor superfamily of cytokines in the pathogenesis of preclinical and human multiple sclerosis: In silico and in vivo evidences. J Neuroimmunol 2018; 322:46-56. [PMID: 29935880 DOI: 10.1016/j.jneuroim.2018.06.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/30/2018] [Accepted: 06/12/2018] [Indexed: 01/05/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions involved in the pathogenesis of autoimmune disorders, including Multiple Sclerosis (MS). We have first evaluated in silico the involvement of MIF, its homologue D-DT, and the receptors CD74, CD44, CXCR2 and CXCR4 in encephalitogenic T cells from a mouse model of MS, the Experimental Allergic Encephalomyelitis (EAE), as well as in circulating T helper cells from MS patients. We show an upregulation of the receptors involved in MIF signaling both in the animal model and in patients. Also, a significant increase in MIF receptors is found in the CNS lesions associated to MS. Finally, the specific inhibitor of MIF, ISO-1, improved both ex vivo and in vivo the features of EAE. Overall, our data indicate that there is a significant involvement of the MIF pathway in MS ethiopathogenesis and that interventions specifically blocking MIF receptors may represent useful therapeutic approaches in the clinical setting.
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Affiliation(s)
- Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | | | - Eugenio Cavalli
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | | | - Maria Cristina Petralia
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; Department of Formative Processes, University of Catania, Catania, Italy
| | - Katia Mangano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Yousef Al-Abed
- Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, New York, United States
| | | | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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22
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Wang X, Sundquist K, Palmér K, Hedelius A, Memon AA, Sundquist J. Macrophage Migration Inhibitory Factor and microRNA-451a in Response to Mindfulness-based Therapy or Treatment as Usual in Patients with Depression, Anxiety, or Stress and Adjustment Disorders. Int J Neuropsychopharmacol 2018; 21:513-521. [PMID: 29373661 PMCID: PMC6007313 DOI: 10.1093/ijnp/pyy001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 01/10/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Macrophage migration inhibitory factor is a proinflammatory cytokine that has been associated with various psychiatric disorders. MicroRNA-451a can directly target macrophage migration inhibitory factor and downregulate its expression in cells. However, the role of macrophage migration inhibitory factor and microRNA-451a in psychiatric patients treated with psychotherapeutic interventions is unknown. In this study, our aim was to investigate levels of macrophage migration inhibitory factor and its regulating microRNA-451a in patients with depression, anxiety, or stress and adjustment disorders who underwent mindfulness-based therapy or treatment as usual. METHODS A total of 168 patients with psychiatric disorders were included from a randomized controlled trial that compared mindfulness-based therapy with treatment as usual. Plasma levels of macrophage migration inhibitory factor and microRNA-451a were measured at baseline and after the 8-week follow-up using Luminex assay and qPCR. RESULTS Macrophage migration inhibitory factor levels decreased significantly in patients posttreatment, whereas microRNA-451a levels showed a nonsignificant change. Macrophage migration inhibitory factor levels were inversely associated with microRNA-451a expression levels at baseline (β=-0.04, P=.008). The change in macrophage migration inhibitory factor levels (follow-up levels minus baseline levels) was associated with the change in microRNA-451a (follow-up levels minus baseline levels) (β=-0.06, P < .0001). The change in either macrophage migration inhibitory factor or microRNA-451a was not associated with improvement in psychiatric symptoms. CONCLUSION We demonstrate that the levels of macrophage migration inhibitory factor decreased after psychotherapeutic interventions in patients with psychiatric disorders. However, this reduction was not associated with an improvement in psychiatric symptoms in response to the treatment. We also found an association between macrophage migration inhibitory factor and its regulating microRNA. However, this association needs to be further examined in future studies.
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Affiliation(s)
- Xiao Wang
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden,Correspondence: Xiao Wang, PhD, Center for Primary Health Care Research, Skåne University Hospital, 205 02 Malmö, Sweden ()
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - Karolina Palmér
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - Anna Hedelius
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - A A Memon
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
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23
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Hirschfeld J, Howait M, Movila A, Parčina M, Bekeredjian-Ding I, Deschner J, Jepsen S, Kawai T. Assessment of the involvement of the macrophage migration inhibitory factor-glucocorticoid regulatory dyad in the expression of matrix metalloproteinase-2 during periodontitis. Eur J Oral Sci 2017; 125:345-354. [PMID: 28776753 DOI: 10.1111/eos.12363] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine and counter-regulator of endogenous glucocorticoids (GCs). It is implicated in acute and chronic inflammatory diseases. This study investigated the role of the MIF-GC regulatory dyad in the expression and release of matrix metalloproteinase-2 (MMP-2) during periodontitis, in vivo and in vitro. In a Mif-knockout (KO) mouse model of ligature-induced periodontitis, gingival tissues and blood were collected and analysed for levels of interleukin-6 (IL-6), MIF, MMP-2, and corticosterone. In addition, human gingival fibroblasts (HGFs) were tested for production of IL-6 and MMP-2 after stimulation with hydrocortisone (HC), MIF, tumour necrosis factor-alpha (TNF-α), or Fusobacterium nucleatum, a pathogen known to elicit immune responses during periodontitis. Wild-type (WT) mice showed a local and systemic increase of MIF levels during inflammation, which was confirmed by increased local IL-6 concentrations. Systemic GC levels were reduced in WT and Mif-KO mice during inflammation, with overall lower concentrations in Mif-KO mice. In vivo and in vitro, MMP-2 production was not dependent on MIF or inflammatory stimuli, but was inhibited by HC. Therefore, MIF does not appear to stimulate expression of MMP-2 in the gingival tissues, whereas GC upregulates MIF and downregulates MMP-2. Our findings further suggest that MIF may regulate systemic GC levels.
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Affiliation(s)
- Josefine Hirschfeld
- Department of Periodontology, Operative and Preventive Dentistry, University Hospital Bonn, Bonn, Germany.,Periodontal Research Group, Birmingham Dental School and Hospital, Birmingham, UK
| | - Mohammed Howait
- Faculty of Dentistry, Department of Endodontics, King AbdulAziz University, Jeddah, Saudi Arabia.,Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA
| | - Alexandru Movila
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.,Harvard University School of Dental Medicine, Boston, MA, USA.,Academy of Sciences of Moldova, Institute of Zoology, Chisinau, Moldova
| | - Marijo Parčina
- Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Isabelle Bekeredjian-Ding
- Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.,Division of Microbiology, Paul-Ehrlich-Institut, Langen, Germany
| | - James Deschner
- Section Experimental Dento-Maxillo-Facial Medicine, University Hospital Bonn, Bonn, Germany
| | - Søren Jepsen
- Department of Periodontology, Operative and Preventive Dentistry, University Hospital Bonn, Bonn, Germany
| | - Toshihisa Kawai
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.,College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
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Macrophage migration inhibitory factor: A multifaceted cytokine implicated in multiple neurological diseases. Exp Neurol 2017; 301:83-91. [PMID: 28679106 DOI: 10.1016/j.expneurol.2017.06.021] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 06/06/2017] [Accepted: 06/21/2017] [Indexed: 12/12/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is a conserved cytokine found as a homotrimer protein. It is found in a wide spectrum of cell types in the body including neuronal and non-neuronal cells. MIF is implicated in several biological processes; chemo-attraction, cytokine activity, and receptor binding, among other functions. More recently, a chaperone-like activity has been added to its repertoire. In this review, we focus on the implication of MIF in the central nervous system and peripheries, its role in neurological disorders, and the mechanisms by which MIF is regulated. Numerous studies have associated MIF with various disease settings. MIF plays an important role in advocating tumorigenic processes, Alzheimer's disease, and is also upregulated in autism-spectrum disorders and spinal cord injury where it contributes to the severity of the injured area. The protective effect of MIF has been reported in amyotrophic lateral sclerosis by its reduction of aggregated misfolded SOD1, subsequently reducing the severity of this disease. Interestingly, a protective as well as pathological role for MIF has been implicated in stroke and cerebral ischemia, as well as depression. Thus, the role of MIF in neurological disorders appears to be diverse with both beneficial and adversary effects. Furthermore, its modulation is rather complex and it is regulated by different proteins, either on a molecular or protein level. This complexity might be dependent on the pathophysiological context and/or cellular microenvironment. Hence, further clarification of its diverse roles in neurological pathologies is warranted to provide new mechanistic insights which may lead in the future to the development of therapeutic strategies based on MIF, to fight some of these neurological disorders.
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Tilstam PV, Qi D, Leng L, Young L, Bucala R. MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics. Expert Opin Ther Targets 2017; 21:671-683. [PMID: 28562118 DOI: 10.1080/14728222.2017.1336227] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia. Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner. Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and autoimmunity.
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Affiliation(s)
- Pathricia V Tilstam
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Dake Qi
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA.,b Department of Biomedical Sciences , Memorial University of Newfoundland , St. John's , Canada
| | - Lin Leng
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Lawrence Young
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Richard Bucala
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
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26
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Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer. Pathol Oncol Res 2016; 23:235-244. [DOI: 10.1007/s12253-016-0138-6] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 10/13/2016] [Indexed: 12/28/2022]
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Brocks T, Fedorchenko O, Schliermann N, Stein A, Moll UM, Seegobin S, Dewor M, Hallek M, Marquardt Y, Fietkau K, Heise R, Huth S, Pfister H, Bernhagen J, Bucala R, Baron JM, Fingerle-Rowson G. Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin. FASEB J 2016; 31:526-543. [PMID: 27825106 DOI: 10.1096/fj.201600860r] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 10/04/2016] [Indexed: 12/29/2022]
Abstract
The response of the skin to harmful environmental agents is shaped decisively by the status of the immune system. Keratinocytes constitutively express and secrete the chemokine-like mediator, macrophage migration inhibitory factor (MIF), more strongly than dermal fibroblasts, thereby creating a MIF gradient in skin. By using global and epidermis-restricted Mif-knockout (Mif-/- and K14-Cre+/tg; Miffl/fl) mice, we found that MIF both recruits and maintains antigen-presenting cells in the dermis/epidermis. The reduced presence of antigen-presenting cells in the absence of MIF was associated with accelerated and increased formation of nonmelanoma skin tumors during chemical carcinogenesis. Our results demonstrate that MIF is essential for maintaining innate immunity in skin. Loss of keratinocyte-derived MIF leads to a loss of control of epithelial skin tumor formation in chemical skin carcinogenesis, which highlights an unexpected tumor-suppressive activity of MIF in murine skin.-Brocks, T., Fedorchenko, O., Schliermann, N., Stein, A., Moll, U. M., Seegobin, S., Dewor, M., Hallek, M., Marquardt, Y., Fietkau, K., Heise, R., Huth, S., Pfister, H., Bernhagen, J., Bucala, R., Baron, J. M., Fingerle-Rowson, G. Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin.
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Affiliation(s)
- Tania Brocks
- Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.,Center for Integrated Oncology Köln-Bonn, Cologne, Germany
| | - Oleg Fedorchenko
- Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.,Center for Integrated Oncology Köln-Bonn, Cologne, Germany
| | - Nicola Schliermann
- Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.,Center for Integrated Oncology Köln-Bonn, Cologne, Germany
| | - Astrid Stein
- Institute of Pathology and Cytology, University Hospital Cologne, Cologne, Germany
| | - Ute M Moll
- Department of Pathology, Stony Brook University, Stony Brook, New York, USA.,Department of Molecular Oncology, Georg-August University, Göttingen Center of Molecular Biosciences, Ernst-Caspari-Haus, Göttingen, Germany
| | - Seth Seegobin
- Department of Medical and Molecular Genetics, School of Medicine, Guy's Hospital, King's College London, London, United Kingdom
| | - Manfred Dewor
- Institute of Biochemistry and Molecular Cell Biology Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Michael Hallek
- Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.,Center for Integrated Oncology Köln-Bonn, Cologne, Germany
| | - Yvonne Marquardt
- Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Katharina Fietkau
- Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Ruth Heise
- Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Sebastian Huth
- Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Herbert Pfister
- Institute of Virology, University Hospital Cologne, Cologne, Germany
| | - Juergen Bernhagen
- Institute of Biochemistry and Molecular Cell Biology Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.,Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; and
| | - Richard Bucala
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jens M Baron
- Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Guenter Fingerle-Rowson
- Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany; .,Center for Integrated Oncology Köln-Bonn, Cologne, Germany
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Macrophage migration inhibitory factor is an endogenous regulator of stress-induced extramedullary erythropoiesis. Histochem Cell Biol 2016; 146:311-24. [DOI: 10.1007/s00418-016-1442-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2016] [Indexed: 12/25/2022]
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29
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Amadori M, Stefanon B, Sgorlon S, Farinacci M. Immune system response to stress factors. ITALIAN JOURNAL OF ANIMAL SCIENCE 2016. [DOI: 10.4081/ijas.2009.s1.287] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Bay-Richter C, Janelidze S, Sauro A, Bucala R, Lipton J, Deierborg T, Brundin L. Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice. J Neuroinflammation 2015; 12:163. [PMID: 26338025 PMCID: PMC4558780 DOI: 10.1186/s12974-015-0387-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 08/24/2015] [Indexed: 01/15/2023] Open
Abstract
Background Evidence from clinical studies and animal models show that inflammation can lead to the development of depression. Macrophage migration inhibitory factor (MIF) is an important multifunctional cytokine that is synthesized by several cell types in the brain. MIF can increase production of other cytokines, activates cyclooxygenase (COX)-2 and can counter-regulate anti-inflammatory effects of glucocorticoids. Increased plasma levels of MIF are associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation and depressive symptoms in patients. In contrast, MIF knockout (KO) mice have been found to exhibit increased depressive-like behaviour. The exact role for MIF in depression is therefore still controversial. To further understand the role of MIF in depression, we studied depressive-like behaviour in congenic male and female MIF KO mice and wild-type (WT) littermates and the associated neurobiological mechanisms underlying the behavioural outcome. Methods MIF KO and WT mice were tested for spontaneous locomotor activity in the open-field test, anhedonia-like behaviour in the sucrose preference test (SPT), as well as behavioural despair in the forced swim test (FST) and tail suspension test (TST). Brain and serum levels of cytokines, the enzymes COX-2 and indoleamine-2,3-dioxygenase (IDO) and the glucocorticoid hormone corticosterone were measured by RT-qPCR and/or high-sensitivity electrochemiluminescence-based multiplex immunoassays. Monoamines and metabolites were examined using HPLC. Results We found that MIF KO mice of both sexes displayed decreased depressive-like behaviour as measured in the FST. In the TST, a similar, but non-significant, trend was also found. IFN-γ levels were decreased, and dopamine metabolism increased in MIF KO mice. Decreased brain IFN-γ levels predicted higher striatal dopamine levels, and high dopamine levels in turn were associated with reduced depressive-like behaviour. In the SPT, there was a sex-specific discrepancy, where male MIF KO mice showed reduced anhedonia-like behaviour whereas female KO mice displayed increased anhedonia-like behaviour. Our results suggest that this relates to the increased corticosterone levels detected in female, but not male, MIF KO mice. Conclusions Our findings support that MIF is involved in the generation of depressive-like symptoms, potentially by the effects of IFN-γ on dopamine metabolism. Our data further suggests a sex-specific regulation of the involved mechanisms.
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Affiliation(s)
- Cecilie Bay-Richter
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark.
| | - Shorena Janelidze
- Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
| | - Analise Sauro
- Department of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA.
| | - Richard Bucala
- Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
| | - Jack Lipton
- Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
| | - Tomas Deierborg
- Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, BMC, Lund University, Lund, Sweden.
| | - Lena Brundin
- Department of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA. .,Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, USA.
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31
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Evaluation of the neutrophil-lymphocyte ratio as a measure of distress in rats. Lab Anim (NY) 2015; 43:276-82. [PMID: 25050728 DOI: 10.1038/laban.529] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 03/25/2014] [Indexed: 01/08/2023]
Abstract
The ability to evaluate distress in laboratory animals is needed in order to ensure that husbandry and experimental procedures do not negatively impact animal welfare. Accurate measurement of acute stress and chronic stress, and distinguishing between stress that is harmful (distress) and stress that does no harm (eustress), can be challenging. Whereas corticosterone concentrations are commonly used to measure stress in laboratory animals, the neutrophil-lymphocyte ratio has been proposed as a potentially better indicator of chronic stress. Furthermore, an association between such measures of stress and concurrent behavioral indicators of negative welfare is required to determine their accuracy in evaluating distress. The authors compared serum corticosterone concentrations and neutrophil-lymphocyte ratios to assess acute or chronic stress in male Sprague Dawley rats. Elevated serum corticosterone concentrations, but not neutrophil-lymphocyte ratios, were associated with acute stress exposure, whereas elevated neutrophil-lymphocyte ratios, but not serum corticosterone concentrations, were associated with chronic stress exposure. Because the neutrophil-lymphocyte ratio differences corresponded with a behavioral indicator of distress in chronically stressed rats, it may serve as a valuable tool for the physiological assessment of distress in rats.
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Ji N, Kovalovsky A, Fingerle-Rowson G, Guentzel MN, Forsthuber TG. Macrophage migration inhibitory factor promotes resistance to glucocorticoid treatment in EAE. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2015; 2:e139. [PMID: 26280015 PMCID: PMC4529283 DOI: 10.1212/nxi.0000000000000139] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Accepted: 06/12/2015] [Indexed: 02/04/2023]
Abstract
Objective: Glucocorticoids (GCs) are used as standard treatment for acute attacks of multiple sclerosis (MS). However, GCs eventually lose efficacy and do not prevent disease progression. Macrophage migration inhibitory factor (MIF) is the only known proinflammatory cytokine induced by GCs that inhibits their anti-inflammatory effects. Therefore, we investigated whether MIF plays a role in resistance to GC treatment in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Methods: EAE was induced in wild-type (Wt) and MIF knockout (MIF−/−) mice followed by treatment with dexamethasone (Dex) before or upon disease onset. Splenocytes and brain mononuclear cells were harvested for cytokine ELISPOT assay and flow cytometry analysis. Results: Treatment of EAE with Dex was substantially more efficacious in MIF−/− mice than Wt mice. Dex treatment decreased MOG35-55–induced cytokine production by Wt or MIF−/− CD4+ T cells only at the onset of EAE but inhibited upregulation of T-bet during acute and chronic phases of disease, particularly in MIF−/− mice. Furthermore, passive EAE induced by adoptive transfer of T cells showed that Dex was highly effective in ameliorating disease induced by MIF−/− CD4+ T cells but not by Wt CD4+ T cells. The expression of T-bet and VLA-4 was decreased in CD4+ T cells in MIF−/− mice compared with Wt mice. Conclusions: Our data establish MIF as a key molecule in resistance of pathogenic CD4+ T cells to GC treatment in EAE and as a potential target to enhance the effectiveness of steroid treatment in neuroinflammatory disorders.
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Affiliation(s)
- Niannian Ji
- Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany
| | - Andra Kovalovsky
- Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany
| | - Günter Fingerle-Rowson
- Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany
| | - M Neal Guentzel
- Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany
| | - Thomas G Forsthuber
- Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany
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Thiele M, Kerschbaumer RJ, Tam FWK, Völkel D, Douillard P, Schinagl A, Kühnel H, Smith J, McDaid JP, Bhangal G, Yu MC, Pusey CD, Cook HT, Kovarik J, Magelky E, Bhan A, Rieger M, Mudde GC, Ehrlich H, Jilma B, Tilg H, Moschen A, Terhorst C, Scheiflinger F. Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions. THE JOURNAL OF IMMUNOLOGY 2015. [PMID: 26209628 DOI: 10.4049/jimmunol.1500572] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy.
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Affiliation(s)
- Michael Thiele
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | | | - Frederick W K Tam
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom
| | - Dirk Völkel
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | - Patrice Douillard
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | - Alexander Schinagl
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | - Harald Kühnel
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | - Jennifer Smith
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom
| | - John P McDaid
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom
| | - Gurjeet Bhangal
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom
| | - Mei-Ching Yu
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom
| | - Charles D Pusey
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom
| | - H Terence Cook
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom
| | - Josef Kovarik
- Department of Nephrology, Wilhelminenspital, 1160 Vienna, Austria
| | - Erica Magelky
- Department of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Atul Bhan
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02214
| | - Manfred Rieger
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | - Geert C Mudde
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | - Hartmut Ehrlich
- Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria
| | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University Vienna, 1090 Vienna, Austria; and
| | - Herbert Tilg
- Department of Internal Medicine I, Endocrinology, Gastroenterology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Alexander Moschen
- Department of Internal Medicine I, Endocrinology, Gastroenterology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Cox Terhorst
- Department of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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Abu-Hamad S, Israelson A. Macrophage migration inhibitory factor as a component of selective vulnerability of motor neurons in ALS. Rare Dis 2015; 3:e1061164. [PMID: 26459694 PMCID: PMC4588549 DOI: 10.1080/21675511.2015.1061164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 06/04/2015] [Accepted: 06/05/2015] [Indexed: 01/08/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons. Mutations in superoxide dismutase (SOD1) cause about 20 percent of familial ALS which is accompanied by accumulation of misfolded SOD1 onto intracellular organelles. Recently, we identified the 12 kDa macrophage migration inhibitory factor (MIF) as a chaperone for mutant SOD1 which is abundant in non-neuronal tissues. Purified recombinant MIF was shown to directly inhibit mutant SOD1 misfolding and association with mitochondria and ER. Elevating MIF in neuronal cells inhibited the accumulation of misfolded SOD1 and its association with mitochondria and ER, and extended survival of mutant SOD1-expressing motor neurons. Our results revealed that the levels of MIF protein are very low in motor neurons, implicating low chaperone activity as a component of selective vulnerability of motor neurons to mutant SOD1 misfolding and toxicity.
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Affiliation(s)
- Salah Abu-Hamad
- Department of Physiology and Cell Biology; Faculty of Health Sciences; The Zlotowski Center for Neuroscience; Ben-Gurion University of the Negev ; Beer Sheva, Israel
| | - Adrian Israelson
- Department of Physiology and Cell Biology; Faculty of Health Sciences; The Zlotowski Center for Neuroscience; Ben-Gurion University of the Negev ; Beer Sheva, Israel
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35
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Sauler M, Bucala R, Lee PJ. Role of macrophage migration inhibitory factor in age-related lung disease. Am J Physiol Lung Cell Mol Physiol 2015; 309:L1-10. [PMID: 25957294 DOI: 10.1152/ajplung.00339.2014] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 05/05/2015] [Indexed: 12/25/2022] Open
Abstract
The prevalence of many common respiratory disorders, including pneumonia, chronic obstructive lung disease, pulmonary fibrosis, and lung cancer, increases with age. Little is known of the host factors that may predispose individuals to such diseases. Macrophage migration inhibitory factor (MIF) is a potent upstream regulator of the immune system. MIF is encoded by variant alleles that occur commonly in the population. In addition to its role as a proinflammatory cytokine, a growing body of literature demonstrates that MIF influences diverse molecular processes important for the maintenance of cellular homeostasis and may influence the incidence or clinical manifestations of a variety of chronic lung diseases. This review highlights the biological properties of MIF and its implication in age-related lung disease.
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Affiliation(s)
- Maor Sauler
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; and
| | - Richard Bucala
- Section of Rheumatology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Patty J Lee
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; and
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36
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Meng Z, Yang X, Hu D, Wang K, Zhi F, Chen X, Gong G, Wu J, Hu Y. Replacing heme with paclitaxel to prepare drug-loaded globin nanoassembles for CD163 targeting. J Pharm Sci 2015; 104:1045-55. [PMID: 25640195 DOI: 10.1002/jps.24290] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 10/27/2014] [Accepted: 10/28/2014] [Indexed: 01/22/2023]
Abstract
Protein-based nanoparticles hold great promises in both preclinical and clinical practices, such as oncology diagnosis and treatment, because of their high biocompatibility and biodegradability. However, the complicated preparation and lack of targeting specific cells or tissues may limit their further uses. To overcome these limitations, we developed a novel replacing method for preparing dual-functional protein nanocarrier, such that one function is capable of encapsulating small molecule into protein, whereas the other function is cable of recognizing CD163 receptor [hemoglobin (Hb) scavenger receptor]. In this study, Hb was chosen as the targeting drug carrier. First, the heme group in the Hb was removed and replaced by paclitaxel (PTX) to form nanoparticles (Gb-NPs-PTX). The resulted Gb-NPs-PTX showed spherical shape and their diameter could be controlled in the range of 120-160 nm by altering the ratio of PTX to Hb. The binding activity of Gb-NPs-PTX to CD163 was confirmed by cell uptake in CD163(+) Chinese hamster ovary cells. Results in vivo also showed a CD163-dependent tissue accumulation of Gb-NPs-PTX in mice. In summary, by using the novel replacing method, PTX could be easily encapsulated into Hb nanoparticles and the targeting effects of Hb could also be kept.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/genetics
- Antigens, Differentiation, Myelomonocytic/metabolism
- Antineoplastic Agents, Phytogenic/administration & dosage
- Antineoplastic Agents, Phytogenic/chemistry
- Antineoplastic Agents, Phytogenic/pharmacokinetics
- Biological Transport
- CHO Cells
- Chemistry, Pharmaceutical
- Cricetulus
- Drug Carriers
- Globins/chemistry
- Globins/metabolism
- Heme/chemistry
- Heme/metabolism
- Mice, Inbred BALB C
- Nanoparticles
- Nanotechnology
- Paclitaxel/administration & dosage
- Paclitaxel/chemistry
- Paclitaxel/pharmacokinetics
- Particle Size
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Technology, Pharmaceutical/methods
- Tissue Distribution
- Transfection
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Affiliation(s)
- Zhengjie Meng
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, People's Republic of China; College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, People's Republic of China
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37
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Bick J, Nguyen V, Leng L, Piecychna M, Crowley MJ, Bucala R, Mayes LC, Grigorenko EL. Preliminary associations between childhood neglect, MIF, and cortisol: potential pathways to long-term disease risk. Dev Psychobiol 2015; 57:131-9. [PMID: 25380347 PMCID: PMC4337818 DOI: 10.1002/dev.21265] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 10/04/2014] [Indexed: 11/06/2022]
Abstract
The study examined Hypothalamus-Pituitary-Adrenal (HPA) axis and inflammatory signaling in 206 youth with histories of prenatal drug exposure and self-reported histories of maltreatment. Youth with histories of severe neglect showed elevated levels of cortisol, the end product of the HPA axis, in comparison to youth with lower or minimal levels of neglect. Histories of severe neglect also were associated with increased levels of Macrophage Migration Inhibitory Factor (MIF), a cytokine known to be intricately involved in HPA axis regulation. Salivary MIF levels also were positively associated with youth age and prenatal drug exposure. These MIF and cortisol alterations may signal pathophysiological disruptions in the neuro-endocrine and immune systems, which may lead to trajectories of increased disease risk among vulnerable youth. Our findings also provide preliminary support for the validity and reliability of a noninvasive salivary assessment of MIF.
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Affiliation(s)
- Johanna Bick
- Child Study Center, Yale School of Medicine, New Haven, CT
| | - Victoria Nguyen
- Child Study Center, Yale School of Medicine, New Haven, CT
- Yale College, New Haven, CT
| | - Lin Leng
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT
| | - Marta Piecychna
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT
| | | | - Richard Bucala
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT
| | - Linda C. Mayes
- Child Study Center, Yale School of Medicine, New Haven, CT
| | - Elena L. Grigorenko
- Child Study Center, Yale School of Medicine, New Haven, CT
- Moscow State University for Psychology, and Education, Moscow, Russia
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38
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Chrousos GP, Zapanti ED. Hypothalamic-pituitary-adrenal axis in HIV infection and disease. Endocrinol Metab Clin North Am 2014; 43:791-806. [PMID: 25169568 DOI: 10.1016/j.ecl.2014.06.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
HIV infection induces hypothalamic-pituitary-adrenal (HPA) axis derangements. Partial glucocorticoid resistance has been observed in a subset of AIDS patients, possibly owing to HIV-induced altered cytokine secretion and action. Because glucocorticoids have immunomodulatory effects, the severity of the HPA axis disorder could play a central role in disease progression. The characteristic phenotype of AIDS patients (visceral obesity, lipodystrophy) may be owing to effects of HIV proteins on the HPA axis, including changes in glucocorticoid and insulin sensitivity of target tissues, as well as altered cytokine production and interaction with the HPA axis, genetic causes, comorbidities, and, possibly, use of antiretroviral agents.
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Affiliation(s)
- George P Chrousos
- First Department of Pediatrics, "Agia Sofia" Children's Hospital, University of Athens, Thivon and Papadiamantopoulou, Athens 11527, Greece
| | - Evangelia D Zapanti
- First Endocrine Department and Diabetes Center, Alexandra Hospital, 80 Vassilisis Sofias Avenue, Athens 11528, Greece.
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39
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Role of MIF in myocardial ischaemia and infarction: insight from recent clinical and experimental findings. Clin Sci (Lond) 2014; 127:149-61. [PMID: 24697297 DOI: 10.1042/cs20130828] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
First discovered in 1966 as an inflammatory cytokine, MIF (macrophage migration inhibitory factor) has been extensively studied for its pivotal role in a variety of inflammatory diseases, including rheumatoid arthritis and atherosclerosis. Although initial studies over a decade ago reported increases in circulating MIF levels following acute MI (myocardial infarction), the dynamic changes in MIF and its pathophysiological significance following MI have been unknown until recently. In the present review, we summarize recent experimental and clinical studies examining the diverse functions of MIF across the spectrum of acute MI from brief ischaemia to post-infarct healing. Following an acute ischaemic insult, MIF is rapidly released from jeopardized cardiomyocytes, followed by a persistent MIF production and release from activated immune cells, resulting in a sustained increase in circulating levels of MIF. Recent studies have documented two distinct actions of MIF following acute MI. In the supra-acute phase of ischaemia, MIF mediates cardioprotection via several distinct mechanisms, including metabolic activation, apoptosis suppression and antioxidative stress. In prolonged myocardial ischaemia, however, MIF promotes inflammatory responses with largely detrimental effects on cardiac function and remodelling. The pro-inflammatory properties of MIF are complex and involve MIF derived from cardiac and immune cells contributing sequentially to the innate immune response evoked by MI. Emerging evidence on the role of MIF in myocardial ischaemia and infarction highlights a significant potential for the clinical use of MIF agonists or antagonists and as a unique cardiac biomarker.
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40
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Assis DN, Leng L, Du X, Zhang CK, Grieb G, Merk M, Garcia AB, McCrann C, Chapiro J, Meinhardt A, Mizue Y, Nikolic-Paterson DJ, Bernhagen J, Kaplan MM, Zhao H, Boyer JL, Bucala R. The role of macrophage migration inhibitory factor in autoimmune liver disease. Hepatology 2014; 59:580-91. [PMID: 23913513 PMCID: PMC3877200 DOI: 10.1002/hep.26664] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 07/28/2013] [Indexed: 01/24/2023]
Abstract
UNLABELLED The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high-expression -794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme-linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls. CONCLUSIONS These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases.
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Affiliation(s)
- David N. Assis
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Lin Leng
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Xin Du
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Clarence K. Zhang
- Department of Biostatistics, Yale School of Public Health, 60 College Street, New Haven, CT 06520, USA
| | - Gerrit Grieb
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA,Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany,Department of Plastic Surgery, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany
| | - Melanie Merk
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Alvaro Baeza Garcia
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Catherine McCrann
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Julius Chapiro
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA,Department of Anatomy and Cell Biology, Justus-Liebig-University, 35385 Giessen, Germany
| | - Andreas Meinhardt
- Department of Anatomy and Cell Biology, Justus-Liebig-University, 35385 Giessen, Germany
| | - Yuka Mizue
- Sapporo Immuno Diagnostic Laboratory, Sapporo, Japan
| | - David J. Nikolic-Paterson
- Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168, Australia
| | - Jürgen Bernhagen
- Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany
| | - Marshall M. Kaplan
- Division of Gastroenterology, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA
| | - Hongyu Zhao
- Department of Biostatistics, Yale School of Public Health, 60 College Street, New Haven, CT 06520, USA
| | - James L. Boyer
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Richard Bucala
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
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41
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Tissue-specific regulation of inflammation by macrophage migration inhibitory factor and glucocorticoids in fructose-fed Wistar rats. Br J Nutr 2013; 110:456-65. [DOI: 10.1017/s0007114512005193] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
High fructose consumption is commonly associated with insulin resistance, disturbed glucose homeostasis and low-grade inflammation. Increased glucocorticoid production within adipose tissue has been implicated in the pathogenesis of fructose-induced metabolic syndrome. Immunosuppressive actions of glucocorticoids can be counter-regulated by macrophage migration inhibitory factor (MIF), which is recognised as a key molecule in metabolic inflammation. In the present study, we hypothesised that coordinated action of glucocorticoids and MIF can mediate the effects of a high-fructose diet on adipose tissue and liver inflammation. We examined the effects of long-term consumption of a 10 % fructose solution on corticosterone (CORT) and MIF levels in rat blood plasma, liver and adipose tissue, as well as MIF and TNF-α mRNA expression and NF-κB activation in the same tissues. The high-fructose diet led to an increase in both CORT and MIF in the adipose tissue, and a highly significant positive correlation between their levels was observed. The attenuated NF-κB activation and unaltered TNF-α mRNA expression noticed in the adipose tissue could be interpreted as an outcome of the opposing actions of CORT and MIF. In contrast to adipose tissue, inflammation in the liver was characterised by NF-κB activation, an increased TNF-α mRNA level and unchanged levels of MIF protein, MIF mRNA and CORT. Overall, these findings suggest that a high-fructose diet differently affects the levels of glucocorticoids and MIF in the adipose tissue and liver, implicating that fructose over-consumption has tissue-specific effects on regulation of metabolic inflammation.
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42
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Xie Q, Wang SC, Bian G, Zhan FL, Xie JK, Li J. Association of MIF-173G/C and MBL2 codon 54 gene polymorphisms with rheumatoid arthritis: a meta-analysis. Hum Immunol 2012; 73:966-71. [PMID: 22820623 DOI: 10.1016/j.humimm.2012.07.043] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 05/24/2012] [Accepted: 07/11/2012] [Indexed: 11/30/2022]
Abstract
The aim of this study was to evaluate the association between macrophage migration inhibitory factor (MIF) -173G/C (rs755622), mannose-binding lectin (MBL2) exon 1 codon 54 (rs1800450) gene polymorphisms and rheumatoid arthritis (RA) susceptibility in ethnically different populations. A meta-analysis was conducted (allelic contrast, the additive model, the dominant model and the recessive model) on the MIF-173G/C polymorphism across five studies (four European and one Asian studies), and the MBL2 codon 54 polymorphism with five studies (four Asian and one European studies), respectively. Meta-analysis indicated an association between the MIF-173G/C in all study subjects in allelic contrast (OR=1.19, 95%CI: 1.05-1.35, P=0.001), the additive model (OR=1.68, 95CI: 1.13-2.49, P=0.001), the dominant model (OR=1.17, 95CI: 1.01-1.35, P=0.003), the recessive model (OR=1.63, 95CI: 1.10-2.42, P=0.001). While stratified by ethnicity with European populations, an association was found in allelic contrast (OR=1.20, 95CI: 1.04-1.38, P=0.002), the additive model (OR=1.85, 95CI: 1.19-2.88, P=0.001), the dominant model (OR=1.20, 95CI: 1.02-1.41, P=0.003). With respect to MBL2 codon 54 polymorphism and RA, no association was found in all study subjects in all comparisons, but there was an association while stratified by ethnicity with Asian populations in the dominant model (OR=1.50, 95CI: 1.01-2.23, P=0.007). In conclusion, the present study suggests that the MIF-173G/C polymorphism is associated with RA susceptibility, but the MBL2 codon 54 polymorphism is not associated with RA.
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Affiliation(s)
- Qiang Xie
- School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, PR China
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43
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Merk M, Mitchell RA, Endres S, Bucala R. D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family. Cytokine 2012; 59:10-7. [PMID: 22507380 PMCID: PMC3367028 DOI: 10.1016/j.cyto.2012.03.014] [Citation(s) in RCA: 136] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Revised: 03/09/2012] [Accepted: 03/16/2012] [Indexed: 12/12/2022]
Abstract
D-dopachrome tautomerase (D-DT) is a newly described cytokine and a member of the macrophage migration inhibitory factor (MIF) protein superfamily. MIF is a broadly expressed pro-inflammatory cytokine that regulates both the innate and the adaptive immune response. MIF activates the MAP kinase cascade, modulates cell migration, and counter-acts the immunosuppressive effects of glucocorticoids. For many cell types, MIF also acts as an important survival or anti-apoptotic factor. Circulating MIF levels are elevated in the serum in different infectious and autoimmune diseases, and neutralization of the MIF protein via antibodies or small molecule antagonists improves the outcome in numerous animal models of human disease. Recently, a detailed investigation of the biological role of the closely homologous protein D-DT, which is encoded by a gene adjacent to MIF, revealed an overlapping functional spectrum with MIF. The D-DT protein also is present in most tissues and circulates in serum at similar concentrations as MIF. D-DT binds the MIF cell surface receptor complex, CD74/CD44, with high affinity and induces similar cell signaling and effector functions. Furthermore, an analysis of the signaling properties of the two proteins showed that they work cooperatively, and that neutralization of D-DT in vivo significantly decreases inflammation. In this review, we highlight the similarities and differences between MIF and D-DT, which we propose to designate "MIF-2", and discuss the implication of D-DT/MIF-2 expression for MIF-based therapies.
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Affiliation(s)
- Melanie Merk
- Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, LMU Munich, Germany
| | | | - Stefan Endres
- Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, LMU Munich, Germany
| | - Richard Bucala
- Internal Medicine Yale University School of Medicine, New Haven, CT, 06520
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44
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Noh SU, Park YM. The effect of green tea polyphenols on macrophage migration inhibitory factor-associated steroid resistance. Br J Dermatol 2012; 166:653-7. [PMID: 22050122 DOI: 10.1111/j.1365-2133.2011.10720.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Recently, evidence has been obtained to suggest that inflammation is provoked through upregulation of macrophage migration inhibitory factor (MIF) expression by steroids. However, little is known regarding the effect of steroids on MIF expression in human keratinocytes and the counter-effect of epigallocatechin-3-gallate (EGCG), a member of the class of green tea polyphenols. OBJECTIVES We determined whether or not steroids cause the upregulation of MIF in human keratinocytes, and if so, whether or not EGCG suppresses MIF upregulation in keratinocytes by steroids. We then assessed the effects of EGCG on MIF-induced Th-related chemokine and cytokine expression in keratinocytes. METHODS HaCaT keratinocytes were first treated with dexamethasone in the presence or absence of EGCG in the culture medium. The keratinocytes were then treated with recombinant human (rh)-MIF in the presence or absence of EGCG in the culture medium. The expression of mRNA and protein in Th-related cytokines and chemokines, including MIF in the keratinocytes, was measured by real-time reverse transcription-polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay. RESULTS Dexamethasone significantly enhanced MIF expression in human keratinocytes, and EGCG significantly downregulated the expression of dexamethasone-induced MIF. EGCG also significantly downregulated rh-MIF-induced expression of Th-related cytokines and chemokines, such as interleukin (IL)-6, IL-18, transforming growth factor-β, CCL17, CCL22 and CXCL10, in human keratinocytes. CONCLUSIONS These results demonstrated that EGCG may have a novel pharmacological effect to prevent steroid-induced tachyphylaxis and inflammation by suppressing the expression of MIF in human keratinocytes.
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Affiliation(s)
- S U Noh
- Department of Dermatology, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Korea
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Parisi MG, Toubiana M, Mangano V, Parrinello N, Cammarata M, Roch P. MIF from mussel: coding sequence, phylogeny, polymorphism, 3D model and regulation of expression. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2012; 36:688-96. [PMID: 22085783 DOI: 10.1016/j.dci.2011.10.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 10/20/2011] [Accepted: 10/28/2011] [Indexed: 05/10/2023]
Abstract
Three macrophage migration inhibitory factor (MIF)-related sequences were identified from a Mytilus galloprovincialis EST library. The consensus sequence included a 5'-UTR of 32 nucleotides, the complete ORF of 345 nucleotides, and a 3'-UTR of 349 nucleotides. As for other MIFs, M. galloprovincialis ORF does not include any signal or C-terminus extensions. The translated sequence of 115 amino acids possesses a molecular mass of 12,681.4, a pI of 6.27 and a stability index of 21.48. Its 3D structure resembles human MIF except for one shorter α-helix. Although evolutionary separated from ticks and vertebrates, Mg-MIF appeared to be closely related to Pinctada fucata and Haliotis, but not to Chlamys farreri and Biomphalaria glabrata. Numerous mutation points were observed within the Mg-MIF ORF, defining 11 amino acid variants within the mussels from Palavas-France and 14 amino acid variants within the mussels from Palermo-Italy. The 2 major variants from Palavas were identical to 2 of the 4 major variants from Palermo. In all the 18 Mg-MIF variants, residues involved in tautomerase and in oxidoreductase activities were conserved. Generally, one mussel expressed 2 Mg-MIF amino acid sequences but with different frequencies of occurrence. Mg-MIF is constitutively expressed principally in hemocytes and in the mantle. In contrast to other animal models, Mg-MIF expression was always down regulated following challenge by bacteria and fungi, confirming previous data obtained with microarray. Down regulation started as soon as 1 h and Mg-MIF expression returned to background 9-48 h after the challenge. Exception was regarding the yeast, Candidaalbicans, down-regulation between 9 and 72 h, suggesting yeast and bacteria-filamentous fungi trigger different mechanisms of elimination.
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Affiliation(s)
- Maria-Giovanna Parisi
- Marine Immunobiology Laboratory, University of Palermo, Via Archirafi 18, 90123 Palermo, Italy
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Kerschbaumer RJ, Rieger M, Völkel D, Le Roy D, Roger T, Garbaraviciene J, Boehncke WH, Müllberg J, Hoet RM, Wood CR, Antoine G, Thiele M, Savidis-Dacho H, Dockal M, Ehrlich H, Calandra T, Scheiflinger F. Neutralization of macrophage migration inhibitory factor (MIF) by fully human antibodies correlates with their specificity for the β-sheet structure of MIF. J Biol Chem 2012; 287:7446-55. [PMID: 22238348 DOI: 10.1074/jbc.m111.329664] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50-68 or 86-102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a β-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this β-sheet structure is a crucial region for MIF activity and a promising target for anti-MIF antibody therapy.
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Okita Y, Miki C, Yoshiyama S, Otake K, Araki T, Uchida K, Kusunoki M. Neutrophil dysfunction in steroid-overdosed patients with ulcerative colitis: potential relevance of macrophage migration inhibitory factor to increased postoperative morbidity. Surg Today 2011; 41:1504-11. [PMID: 21969153 DOI: 10.1007/s00595-010-4505-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Accepted: 08/24/2010] [Indexed: 12/15/2022]
Abstract
PURPOSE We studied macrophage migration inhibitory factor (MIF)-related neutrophil dysfunction in patients with ulcerative colitis (UC), under conditions of surgical stress, focusing in particular on total preoperative steroid dosages. METHODS Neutrophils were isolated from peripheral blood samples obtained from 21 UC patients soon after radical surgery for UC. The patients were divided into two subgroups according to their total preoperative prednisolone dosages. The neutrophil phagocytosis, viable cell, and cell necrosis rates after exposure to Escherichia coli were evaluated by flow cytometry. The supernatant concentrations of mediators after exposure to E. coli were evaluated by enzyme-linked immunosorbent assay. RESULTS There was a significant positive correlation between the levels of MIF and the total preoperative dosage of prednisolone. More viable neutrophils from the high-dosage steroid group patients than from the low-dosage steroid group patients tended to undergo necrosis, followed by the release of neutrophil elastase after exposure to E. coli. The levels of anti-inflammatory cytokines were not enhanced after E. coli stimulation, but the levels of proinflammatory cytokines in the supernatants of neutrophils from the high-dosage steroid group patients were increased significantly. CONCLUSION Steroid-overdosed UC patients with MIF-related neutrophil dysfunction may be at increased risk of destructive local inflammation following surgery.
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Affiliation(s)
- Yoshiki Okita
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
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Gilliver SC, Emmerson E, Bernhagen J, Hardman MJ. MIF: a key player in cutaneous biology and wound healing. Exp Dermatol 2011; 20:1-6. [PMID: 21158933 DOI: 10.1111/j.1600-0625.2010.01194.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Owing to its implication in a range of pathological conditions, including asthma, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and cancer, the pleiotropic cytokine macrophage migration inhibitory factor (MIF) has been the subject of intensive recent investigation. In the field of dermatology, MIF is believed to be a detrimental factor in diseases such as systemic sclerosis, atopic dermatitis, psoriasis, eczema and UV radiation damage. However, its contribution to other aspects of cutaneous biology is currently unclear. Although its expression in intact skin is well characterized, little is known about MIF's role in cutaneous homoeostasis. However, recent data do identify MIF as a key player in the immune privilege of hair follicles. Similarly, although MIF is rapidly released and its local expression significantly induced upon wounding, its primary role in the ensuing repair process remains a source of contention. MIF has been identified as being a key effector of the beneficial effects of estrogen on wound repair, yet studies employing Mif null mice, recombinant MIF, and neutralizing anti-MIF antibodies have failed to provide a consensus as to whether it benefits or inhibits healing. In fact MIF appears to be able to exert both positive and negative effects, with the cell-specific relevancy of MIF in wound healing still unclear. Thus, if MIF and/or its downstream targets are to be therapeutically useful in the context of cutaneous repair, more needs to be done to establish the nature and mechanism of action of MIF and its receptors in healing wounds.
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Li F, Huang S, Wang L, Yang J, Zhang H, Qiu L, Li L, Song L. A macrophage migration inhibitory factor like gene from scallop Chlamys farreri: Involvement in immune response and wound healing. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2011; 35:62-71. [PMID: 20804783 DOI: 10.1016/j.dci.2010.08.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Revised: 08/04/2010] [Accepted: 08/20/2010] [Indexed: 05/29/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is an evolutionarily ancient and highly conserved cytokine with multiple functions. In the present study, a MIF-like gene was cloned from Zhikong scallop Chlamys farreri (designated as CfMIF) based on expressed sequence tag (EST) analysis and rapid amplification of cDNA ends (RACE) approach. The full-length cDNA of CfMIF was of 2296bp, consisting of a 5' untranslated region (UTR) of 60bp, a 3' UTR of 1903bp with a poly(A) tail and an open reading frame (ORF) of 333bp encoded 111 amino acid residues with a calculated molecular mass of 12.6kDa and a theoretical isoelectric point of 5.63. The deduced amino acid sequence of CfMIF shared 27-50.5% similarity with those of other known MIFs. A conserved MIF domain was identified in the deduced amino acid sequence of CfMIF, and conserved proline(2) and lysine(33) were also found to be present in CfMIF. Phylogenetic analysis revealed that CfMIF is one of MIF members. The tissue distribution and temporal expression of CfMIF in hemocytes of scallop after lipopolysaccharide (LPS), peptidoglycan (PGN) and β-glucan stimulation were detected by real-time RT-PCR. CfMIF gene was ubiquitously expressed in six selected tissues of healthy scallops, with the higher expression levels in hepatopancreas, mantle and gill. In comparison with the control group, the expression of CfMIF mRNA in hemocytes was up-regulated significantly at 6h, 24h and 48h after LPS treatment, and at all time points after PGN and glucan treatment. The cDNA fragment encoding mature peptide of CfMIF was recombined and expressed in Escherichia coli BL21 (DE3) pLysS. The recombinant protein of CfMIF (rCfMIF) promoted sheep fibroblast migration into scraped spaces in vitro. These results generated from the present study encourage us to suggest that CfMIF was a novel member of MIF family, and it was involved in immune response and wound healing by promoting fibroblast migration.
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Affiliation(s)
- Fengmei Li
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071, China
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Macrophage migration inhibitory factor: a multifunctional cytokine in rheumatic diseases. ARTHRITIS 2010; 2010:106202. [PMID: 22046508 PMCID: PMC3195319 DOI: 10.1155/2010/106202] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Revised: 12/04/2010] [Accepted: 12/21/2010] [Indexed: 01/01/2023]
Abstract
Macrophage migration inhibitory factor (MIF) was originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibited the random migration of macrophages. MIF is now recognized to be a multipotent cytokine involved in the regulation of immune and inflammatory responses. Moreover, the pivotal nature of its involvement highlights the importance of MIF to the pathogenesis of various inflammatory disorders and suggests that blocking MIF may be a useful therapeutic strategy for treating these diseases. This paper discusses the function and expressional regulation of MIF in several rheumatic diseases and related conditions.
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