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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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Sasamoto N, Ngo L, Vitonis AF, Dillon ST, Prasad P, Laufer MR, As-Sanie S, Schrepf A, Missmer SA, Libermann TA, Terry KL. Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis. Am J Obstet Gynecol 2024; 231:240.e1-240.e11. [PMID: 38462144 PMCID: PMC11975416 DOI: 10.1016/j.ajog.2024.03.005] [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: 11/22/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.
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Affiliation(s)
- Naoko Sasamoto
- Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA.
| | - Long Ngo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Allison F Vitonis
- Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA
| | - Simon T Dillon
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA
| | | | - Marc R Laufer
- Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA; Division of Gynecology, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Sawsan As-Sanie
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI
| | - Andrew Schrepf
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI
| | - Stacey A Missmer
- Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA; Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, MI; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Towia A Libermann
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA
| | - Kathryn L Terry
- Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
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Breidung D, Megas IF, Freytag DL, Bernhagen J, Grieb G. The Role of Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (D-DT/MIF-2) in Infections: A Clinical Perspective. Biomedicines 2023; 12:2. [PMID: 38275363 PMCID: PMC10813530 DOI: 10.3390/biomedicines12010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024] Open
Abstract
Macrophage migration inhibitory factor (MIF) and its homolog, D-dopachrome tautomerase (D-DT), are cytokines that play critical roles in the immune response to various infectious diseases. This review provides an overview of the complex involvement of MIF and D-DT in bacterial, viral, fungal, and parasitic infections. The role of MIF in different types of infections is controversial, as it has either a protective function or a host damage-enhancing function depending on the pathogen. Depending on the specific role of MIF, different therapeutic options for MIF-targeting drugs arise. Human MIF-neutralizing antibodies, anti-parasite MIF antibodies, small molecule MIF inhibitors or MIF-blocking peptides, as well as the administration of exogenous MIF or MIF activity-augmenting small molecules have potential therapeutic applications and need to be further explored in the future. In addition, MIF has been shown to be a potential biomarker and therapeutic target in sepsis. Further research is needed to unravel the complexity of MIF and D-DT in infectious diseases and to develop personalized therapeutic approaches targeting these cytokines. Overall, a comprehensive understanding of the role of MIF and D-DT in infections could lead to new strategies for the diagnosis, treatment, and management of infectious diseases.
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Affiliation(s)
- David Breidung
- Department of Plastic, Reconstructive and Hand Surgery, Burn Center for Severe Burn Injuries, Klinikum Nuremberg Hospital, Paracelsus Medical University, Breslauer Str. 201, 90471 Nuremberg, Germany;
| | - Ioannis-Fivos Megas
- Department of Orthopaedic and Trauma Surgery, Center of Plastic Surgery, Hand Surgery and Microsurgery, Evangelisches Waldkrankenhaus Spandau, Stadtrandstr. 555, 13589 Berlin, Germany;
| | - David Lysander Freytag
- Department of Plastic Surgery and Hand Surgery, Gemeinschaftskrankenhaus Havelhoehe, Kladower Damm 221, 14089 Berlin, Germany;
| | - Jürgen Bernhagen
- Division of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Feodor-Lynenstraße 17, 81377 Munich, Germany;
- Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynenstraße 17, 81377 Munich, Germany
| | - Gerrit Grieb
- Department of Plastic Surgery and Hand Surgery, Gemeinschaftskrankenhaus Havelhoehe, Kladower Damm 221, 14089 Berlin, Germany;
- Department of Plastic Surgery and Hand Surgery, Burn Center, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
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Thiele M, Donnelly SC, Mitchell RA. OxMIF: a druggable isoform of macrophage migration inhibitory factor in cancer and inflammatory diseases. J Immunother Cancer 2022; 10:e005475. [PMID: 36180072 PMCID: PMC9528626 DOI: 10.1136/jitc-2022-005475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2022] [Indexed: 11/04/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of cancer and inflammatory diseases. MIF is constitutively present in several cell types and non-lymphoid tissues and is secreted after acute stress or inflammation. MIF triggers the release of proinflammatory cytokines, overrides the anti-inflammatory effects of glucocorticoids, and exerts chemokine function, resulting in increased migration and recruitment of leukocytes into inflamed tissue. Despite this, MIF is a challenging target for therapeutic intervention because of its ubiquitous nature and presence in the circulation and tissue of healthy individuals. Oxidized MIF (oxMIF) is an immunologically distinct disease-related structural isoform found in the plasma and tissues of patients with inflammatory diseases and in solid tumor tissues. MIF converts to oxMIF in an oxidizing, inflammatory environment. This review discusses the biology and activity of MIF and the potential for autoimmune disease and cancer modification by targeting oxMIF. Anti-oxMIF antibodies reduce cancer cell invasion/migration, angiogenesis, proinflammatory cytokine production, and ERK and AKT activation. Anti-oxMIF antibodies also elicit apoptosis and alter immune cell function and/or migration. When co-administered with a glucocorticoid, anti-oxMIF antibodies produced a synergistic response in inflammatory models. Anti-oxMIF antibodies therefore counterregulate biological activities attributed to MIF. oxMIF expression has been observed in inflammatory diseases (eg, sepsis, psoriasis, asthma, inflammatory bowel disease, and systemic lupus erythematosus) and oxMIF has been detected in ovarian, colorectal, lung, and pancreatic cancers. In contrast to MIF, oxMIF is specifically detected in plasma and/or tissues of diseased patients, but not in healthy individuals. Therefore, as a druggable isoform of MIF, oxMIF represents a potential new therapeutic target in inflammatory diseases and cancer. Fully human, monoclonal anti-oxMIF antibodies have been shown to selectively bind oxMIF in preclinical and phase I studies; however, additional clinical assessments are necessary to validate their use as either a monotherapy or in combination with standard-of-care regimens (ie, immunomodulatory agents/checkpoint inhibitors, anti-angiogenic drugs, chemotherapeutics, and glucocorticoids).
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Affiliation(s)
- Michael Thiele
- Biology Research, OncoOne Research & Development GmbH, Vienna, Austria
| | - Seamas C Donnelly
- Department of Medicine, Tallaght University Hospital & Trinity College Dublin, Dublin, Ireland
| | - Robert A Mitchell
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky, USA
- Department of Surgery, J.G. Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
- Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, Kentucky, USA
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Harjacek M. Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The "Out of the Box" View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF). Front Med (Lausanne) 2021; 8:700982. [PMID: 34692718 PMCID: PMC8526544 DOI: 10.3389/fmed.2021.700982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 09/06/2021] [Indexed: 12/11/2022] Open
Abstract
Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial-entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.
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Affiliation(s)
- Miroslav Harjacek
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Sorour NE, Hamed AM, Tabl HAEM, Ahmed AAEA. Assessment of macrophage migration inhibitory factor in patients with verruca vulgaris. Clin Cosmet Investig Dermatol 2019; 12:591-595. [PMID: 31686887 PMCID: PMC6709820 DOI: 10.2147/ccid.s209269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/30/2019] [Indexed: 11/23/2022]
Abstract
Background Common warts are caused by human papillomaviruses (HPVs), they are among the most common cutaneous viral infections. Macrophage migration inhibitory factor (MIF) is an essential contributor in many inflammatory and immune skin diseases. Yet, its role in the pathology of common warts is unclear. Objective To assess MIF levels in lesional and perilesional skin in patients with common warts in comparison to apparently healthy control group with matching age and sex. Subjects and methods A case-control study performed on 60 patients with common warts (group A) and 30 age and sex matching healthy controls (group B). Two biopsies were taken from each patient in group A; one from the lesion (lesional) and the other one from the skin around the wart (perilesional), while biopsies of controls were taken from matched sites to patients. Measurement of MIF in all groups was done by quantitative ELISA kits. Results Significant high MIF levels were detected in lesional and perilesional skin biopsies compared to controls (P<0.001). Yet, the difference in MIF levels between lesional and perilesional skin biopsy was non-significant. No significant relations were found between lesional and perilesional MIF levels and clinical characteristics of the studied patients while both lesional and perilesional MIF levels were significantly correlated (rh=0.269, P=0.021). Conclusion The significantly elevated MIF levels in lesional and perilesional skin biopsies compared to controls point to its role in wart progression from HPV infected cells.
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Affiliation(s)
- Neveen Emad Sorour
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Benha Univesity, Benha, Egypt
| | - Ahmed Mohamed Hamed
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Benha Univesity, Benha, Egypt
| | - Hala Abd-El Mageed Tabl
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Benha Univesity, Benha, Egypt
| | - Amira Abd-El Aziz Ahmed
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Benha Univesity, Benha, Egypt
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Hernández-Palma LA, García-Arellano S, Bucala R, Llamas-Covarrubias MA, De la Cruz-Mosso U, Oregon-Romero E, Cerpa-Cruz S, Parra-Rojas I, Plascencia-Hernández A, Muñoz-Valle JF. Functional MIF promoter haplotypes modulate Th17-related cytokine expression in peripheral blood mononuclear cells from control subjects and rheumatoid arthritis patients. Cytokine 2019; 115:89-96. [DOI: 10.1016/j.cyto.2018.11.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 12/21/2022]
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Gow DJ, Jackson H, Forsythe P, Gow AG, Mellanby RJ, Hume DA, Nuttall T. Measurement of serum macrophage migration inhibitory factor (MIF) and correlation with severity and pruritus scores in client owned dogs with atopic dermatitis. Vet Dermatol 2019; 30:115. [PMID: 30672038 DOI: 10.1111/vde.12721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND Atopic dermatitis (AD) is a common inflammatory skin disease of dogs. Macrophage migration inhibitory factor (MIF) initiates pro-inflammatory cytokine release in human AD and serum concentrations are correlated with disease severity. HYPOTHESIS Canine serum MIF concentrations are increased in dogs with AD and correlate with clinical lesion and pruritus scores. ANIMALS Client owned dogs (n = 49) diagnosed with AD and 17 healthy, unaffected control dogs were used for the study. METHODS AND MATERIALS A commercially available MIF ELISA was optimized for the dog and serum from clinical cases used. Information regarding treatment, Canine Atopic Dermatitis Extent and Severity Index, (CADESI-4) and pruritus Visual Analog Scale (pVAS) were recorded for each dog at the time of serum collection. RESULTS Dogs with AD which had not received steroid therapy and those treated with oclacitinib had significantly elevated serum MIF concentrations compared to controls. Concentrations of MIF were not significantly different in AD dogs receiving steroids compared to controls. There was no significant correlation between MIF concentrations and clinical scores (CADESI-4 or pVAS). CONCLUSIONS AND CLINICAL IMPORTANCE Serum MIF concentrations are increased in dogs with AD and MIF might be a target for therapy.
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Affiliation(s)
- Debbie J Gow
- R(D)SVS and The Roslin Institute, Hospital for Small Animals, The University of Edinburgh, Edinburgh, EH25 9RG, Scotland, UK
| | - Hilary Jackson
- The Dermatology Referral Service Ltd, 528 Paisley Road West, Glasgow, G51 1RN, Scotland, UK
| | - Peter Forsythe
- The Dermatology Referral Service Ltd, 528 Paisley Road West, Glasgow, G51 1RN, Scotland, UK
| | - Adam G Gow
- R(D)SVS and The Roslin Institute, Hospital for Small Animals, The University of Edinburgh, Edinburgh, EH25 9RG, Scotland, UK
| | - Richard J Mellanby
- R(D)SVS and The Roslin Institute, Hospital for Small Animals, The University of Edinburgh, Edinburgh, EH25 9RG, Scotland, UK
| | - David A Hume
- R(D)SVS and The Roslin Institute, Hospital for Small Animals, The University of Edinburgh, Edinburgh, EH25 9RG, Scotland, UK
- Mater Research Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Tim Nuttall
- R(D)SVS and The Roslin Institute, Hospital for Small Animals, The University of Edinburgh, Edinburgh, EH25 9RG, Scotland, UK
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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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Molecular mechanisms of glucocorticoid resistance in systemic lupus erythematosus: A review. Life Sci 2018; 209:383-387. [PMID: 30125579 DOI: 10.1016/j.lfs.2018.08.038] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 07/14/2018] [Accepted: 08/14/2018] [Indexed: 12/23/2022]
Abstract
The treatment of systemic lupus erythematosus (SLE) with glucocorticoids (GCs) is quite effective; however, GC resistance or insensitivity is a major barrier to the treatment of SLE. Therefore, it is necessary to identify the underlying mechanisms that lead to GC resistance. Much evidence shows that the mechanism of GC resistance is very complicated. GC receptor is involved in the main mechanism of GC resistance and was illustrated by a lot of literature. Therefore, this paper focuses on the GC resistance mechanisms of non-glucocorticoids receptor, including P-gp, MIF, TLR9, and Th17 cells. These molecular mechanisms may help diagnose GC resistance and provide an alternative treatment strategy to reverse GC resistance by blocking the underlying mechanisms.
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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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Lopizzo N, Tosato S, Begni V, Tomassi S, Cattane N, Barcella M, Turco G, Ruggeri M, Riva MA, Pariante CM, Cattaneo A. Transcriptomic analyses and leukocyte telomere length measurement in subjects exposed to severe recent stressful life events. Transl Psychiatry 2017; 7:e1042. [PMID: 28221367 PMCID: PMC5438034 DOI: 10.1038/tp.2017.5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 11/23/2016] [Accepted: 12/08/2016] [Indexed: 02/07/2023] Open
Abstract
Stressful life events occurring in adulthood have been found able to affect mood and behavior, thus increasing the vulnerability for several stress-related psychiatric disorders. However, although there is plenty of clinical data supporting an association between stressful life events in adulthood and an enhanced vulnerability for psychopathology, the underlying molecular mechanisms are still poorly investigated. Thus, in this study we performed peripheral/whole-genome transcriptomic analyses in blood samples obtained from 53 adult subjects characterized for recent stressful life events occurred within the previous 6 months. Transcriptomic data were analyzed using Partek Genomics Suite; pathway and network analyses were performed using Ingenuity Pathway Analysis and GeneMANIA Software. We found 207 genes significantly differentially expressed in adult subjects who reported recent stressful life experiences (n=21) compared with those without such experiences (n=32). Moreover, the same subjects exposed to such stressful experiences showed a reduction in leukocyte telomere length. A correlation analyses between telomere length and transcriptomic data indicated an association between the exposures to recent stressful life events and the modulation of several pathways, mainly involved in immune-inflammatory-related processes and oxidative stress, such as natural killer cell signaling, interleukin-1 (IL-1) signaling, MIF regulation of innate immunity and IL-6 signaling. Our data suggest an association between exposures to recent stressful life events in adulthood and alterations in the immune, inflammatory and oxidative stress pathways, which could be also involved in the negative effect of stressful life events on leukocyte telomere length. The modulation of these mechanisms may underlie the clinical association between the exposure to recent Stressful life events in adulthood and an enhanced vulnerability to develop psychiatric diseases in adulthood.
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Affiliation(s)
- N Lopizzo
- Biological Psychiatry Unit, IRCCS Fatebenefratelli S. Giovanni di Dio, Brescia, Italy
| | - S Tosato
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy
| | - V Begni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - S Tomassi
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy
| | - N Cattane
- Biological Psychiatry Unit, IRCCS Fatebenefratelli S. Giovanni di Dio, Brescia, Italy
| | - M Barcella
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy
| | - G Turco
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy
| | - M Ruggeri
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy
| | - M A Riva
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - C M Pariante
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College, London, London, UK
| | - A Cattaneo
- Biological Psychiatry Unit, IRCCS Fatebenefratelli S. Giovanni di Dio, Brescia, Italy,Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College, London, London, UK,Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK. E-mail:
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Luo QQ, Qian ZM, Zhou YF, Zhang MW, Wang D, Zhu L, Ke Y. Expression of Iron Regulatory Protein 1 Is Regulated not only by HIF-1 but also pCREB under Hypoxia. Int J Biol Sci 2016; 12:1191-1202. [PMID: 27766034 PMCID: PMC5069441 DOI: 10.7150/ijbs.16437] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
The inconsistent of responses of IRP1 and HIF-1 alpha to hypoxia and the similar tendencies in the changes of IRP1 and pCREB contents led us to hypothesize that pCREB might be involved in the regulation of IRP1 under hypoxia. Here, we investigated the role of pCREB in IRP1 expression in HepG2 cells under hypoxia using quantitative PCR, western blot, immunofluorescence, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). We demonstrated that 1) Hypoxia increased pCREB levels inside of the nucleus; 2) Putative CREs were found in the IRP1 gene; 3) Nuclear extracts of HepG2 cells treated with hypoxia could bind to CRE1 and CRE3, and 100-fold competitor of putative CREs could abolish the binding activity to varying degrees; 4) pCREB was found in the CRE1 and CRE3 DNA-protein complexes of EMSA; 5) CRE1 and CRE3 binding activity of IRP1 depended on CREB activation but not on HIF-1; 6) Increased IRP1 expression under hypoxia could be prevented by LY294002; 7) ChIP assays demonstrated that pCREB binds to IRP1 promoter; and 8) HIF-1 and/or HIF-2 siRNA had no effect on the expression of pCREB and IRP1 proteins in cells treated with hypoxia for 8 hours. Our findings evidenced for the involvement of pCREB in IRP1 expression and revealed a dominant role of PI3K/Akt pathway in CREB activation under hypoxia and also suggested that dual-regulation of IRP1 expression by HIF-1 and pCERB or other transcription factor(s) under hypoxia might be a common mechanism in most if not all of hypoxia-inducible genes.
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Affiliation(s)
- Qian-Qian Luo
- Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong, 226001, China; Laboratory of Neuropharmacology, FudanUniversity School of Pharmacy,826 Zhang Heng Road, Pu Dong, Shanghai201203, China
| | - Zhong-Ming Qian
- Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong, 226001, China; Laboratory of Neuropharmacology, FudanUniversity School of Pharmacy,826 Zhang Heng Road, Pu Dong, Shanghai201203, China
| | - Yu-Fu Zhou
- Laboratory of Neuropharmacology, FudanUniversity School of Pharmacy,826 Zhang Heng Road, Pu Dong, Shanghai201203, China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, NT, Hong Kong
| | - Meng-Wan Zhang
- Laboratory of Neuropharmacology, FudanUniversity School of Pharmacy,826 Zhang Heng Road, Pu Dong, Shanghai201203, China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, NT, Hong Kong
| | - Dang Wang
- Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong, 226001, China
| | - Li Zhu
- Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong, 226001, China
| | - Ya Ke
- Laboratory of Neuropharmacology, FudanUniversity School of Pharmacy,826 Zhang Heng Road, Pu Dong, Shanghai201203, China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, NT, Hong Kong
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Trevisi E, Bertoni G. Some physiological and biochemical methods for acute and chronic stress evaluationin dairy cows. ITALIAN JOURNAL OF ANIMAL SCIENCE 2016. [DOI: 10.4081/ijas.2009.s1.265] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Lankford L, Selby T, Becker J, Ryzhuk V, Long C, Farmer D, Wang A. Early gestation chorionic villi-derived stromal cells for fetal tissue engineering. World J Stem Cells 2015; 7:195-207. [PMID: 25621120 PMCID: PMC4300931 DOI: 10.4252/wjsc.v7.i1.195] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/04/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the potential for early gestation placenta-derived mesenchymal stromal cells (PMSCs) for fetal tissue engineering. METHODS PMSCs were isolated from early gestation chorionic villus tissue by explant culture. Chorionic villus sampling (CVS)-size tissue samples (mean = 35.93 mg) were used to test the feasibility of obtaining large cell numbers from CVS within a clinically relevant timeframe. We characterized PMSCs isolated from 6 donor placentas by flow cytometry immunophenotyping, multipotency assays, and through immunofluorescent staining. Protein secretion from PMSCs was examined using two cytokine array assays capable of probing for over 70 factors in total. Delivery vehicle compatibility of PMSCs was determined using three common scaffold systems: fibrin glue, collagen hydrogel, and biodegradable nanofibrous scaffolds made from a combination of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA). Viral transduction of PMSCs was performed using a Luciferase-GFP-containing lentiviral vector and efficiency of transduction was tested by fluorescent microscopy and flow cytometry analysis. RESULTS We determined that an average of 2.09 × 10(6) (SD ± 8.59 × 10(5)) PMSCs could be obtained from CVS-size tissue samples within 30 d (mean = 27 d, SD ± 2.28), indicating that therapeutic numbers of cells can be rapidly expanded from very limited masses of tissue. Immunophenotyping by flow cytometry demonstrated that PMSCs were positive for MSC markers CD105, CD90, CD73, CD44, and CD29, and were negative for hematopoietic and endothelial markers CD45, CD34, and CD31. PMSCs displayed trilineage differentiation capability, and were found to express developmental transcription factors Sox10 and Sox17 as well as neural-related structural proteins NFM, Nestin, and S100β. Cytokine arrays revealed a robust and extensive profile of PMSC-secreted cytokines and growth factors, and detected 34 factors with spot density values exceeding 10(3). Detected factors had widely diverse functions that include modulation of angiogenesis and immune response, cell chemotaxis, cell proliferation, blood vessel maturation and homeostasis, modulation of insulin-like growth factor activity, neuroprotection, extracellular matrix degradation and even blood coagulation. Importantly, PMSCs were also determined to be compatible with both biological and synthetic material-based delivery vehicles such as collagen and fibrin hydrogels, and biodegradable nanofiber scaffolds made from a combination of PLA and PLGA. Finally, we demonstrated that PMSCs can be efficiently transduced (> 95%) with a Luciferase-GFP-containing lentiviral vector for future in vivo cell tracking after transplantation. CONCLUSION Our findings indicate that PMSCs represent a unique source of cells that can be effectively utilized for in utero cell therapy and tissue engineering.
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Affiliation(s)
- Lee Lankford
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Taryn Selby
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - James Becker
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Volodymyr Ryzhuk
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Connor Long
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Diana Farmer
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| | - Aijun Wang
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
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Pearson RM, Juettner VV, Hong S. Biomolecular corona on nanoparticles: a survey of recent literature and its implications in targeted drug delivery. Front Chem 2014; 2:108. [PMID: 25506050 PMCID: PMC4245918 DOI: 10.3389/fchem.2014.00108] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 11/11/2014] [Indexed: 02/03/2023] Open
Abstract
Achieving controlled cellular responses of nanoparticles (NP) is critical for the successful development and translation of NP-based drug delivery systems. However, precise control over the physicochemical and biological properties of NPs could become convoluted, diminished, or completely lost as a result of the adsorption of biomolecules to their surfaces. Characterization of the formation of the "biomolecular" corona has thus received increased attention due to its impact on NP and protein structure as well as its negative effect on NP-based targeted drug delivery. This review presents a concise survey of the recent literature concerning the importance of the NP-biomolecule corona and how it can be utilized to improve the in vivo efficacy of targeted delivery systems.
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Affiliation(s)
- Ryan M. Pearson
- Department of Biopharmaceutical Sciences, University of Illinois at ChicagoChicago, IL, USA
| | - Vanessa V. Juettner
- Department of Biopharmaceutical Sciences, University of Illinois at ChicagoChicago, IL, USA
| | - Seungpyo Hong
- Department of Biopharmaceutical Sciences, University of Illinois at ChicagoChicago, IL, USA
- Department of Bioengineering, University of Illinois at ChicagoChicago, IL, USA
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17
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Sherma ND, Borges CR, Trenchevska O, Jarvis JW, Rehder DS, Oran PE, Nelson RW, Nedelkov D. Mass Spectrometric Immunoassay for the qualitative and quantitative analysis of the cytokine Macrophage Migration Inhibitory Factor (MIF). Proteome Sci 2014; 12:52. [PMID: 25328446 PMCID: PMC4201675 DOI: 10.1186/s12953-014-0052-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 10/02/2014] [Indexed: 12/31/2022] Open
Abstract
Background The cytokine MIF (Macrophage Migration Inhibitory Factor) has diverse physiological roles and is present at elevated concentrations in numerous disease states. However, its molecular heterogeneity has not been previously investigated in biological samples. Mass Spectrometric Immunoassay (MSIA) may help elucidate MIF post-translational modifications existing in vivo and provide additional clarity regarding its relationship to diverse pathologies. Results In this work, we have developed and validated a fully quantitative MSIA assay for MIF, and used it in the discovery and quantification of different proteoforms of MIF in serum samples, including cysteinylated and glycated MIF. The MSIA assay had a linear range of 1.56-50 ng/mL, and exhibited good precision, linearity, and recovery characteristics. The new assay was applied to a small cohort of human serum samples, and benchmarked against an MIF ELISA assay. Conclusions The quantitative MIF MSIA assay provides a sensitive, precise and high throughput method to delineate and quantify MIF proteoforms in biological samples.
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Affiliation(s)
- Nisha D Sherma
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA
| | - Chad R Borges
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA ; Department of Chemistry & Biochemistry at Arizona State University, Tempe, AZ 85287 USA
| | - Olgica Trenchevska
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA
| | - Jason W Jarvis
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA
| | - Douglas S Rehder
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA
| | - Paul E Oran
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA
| | - Randall W Nelson
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA
| | - Dobrin Nedelkov
- The Biodesign Institute at Arizona State University, Tempe, AZ 85287 USA
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18
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The critical role of macrophage migration inhibitory factor in insulin activity. Cytokine 2014; 69:39-46. [PMID: 25022960 DOI: 10.1016/j.cyto.2014.05.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 04/22/2014] [Accepted: 05/12/2014] [Indexed: 12/12/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is a molecule with plethora of functions such as regulation of immune response, hormone-like, enzymatic and chaperone-like activity. Further, MIF is a major participant in glucose homeostasis since it is an autocrine stimulator of insulin secretion. MIF absence in male knockout mice (MIF-KO) results in development of glucose intolerance, while sensitivity to insulin is fully preserved. Since our results confirm that beta cells from MIF-KO mice express, produce and secrete insulin similarly to beta cells of their wild type (WT) counterparts C57BL/6 mice, we hypothesize that MIF-KO-derived insulin is less active. Indeed, insulin from MIF-KO islets is unable to significantly induce glucose uptake into hepatocytes and to efficiently promote insulin-triggered Akt phosphorylation determined by immunoblot. However, MIF's tautomerase function is not crucial for insulin biosynthesis since MIF inhibitors had no impact on WT insulin activity. Importantly, MIF recognition by anti-MIF antibody (ELISA) after in vitro co-incubation with purified insulin was significantly lower suggesting that insulin covers MIF immunodominant epitope. In addition, MIF binds insulin within beta cell as confirmed by co-immunoprecipitation. WT and MIF-KO-derived insulin exhibited different cleavage patterns suggesting different protein conformations. Finally, pre-incubation of recombinant MIF with insulin promotes formation of insulin hexamers. These results imply that MIF probably enables proper insulin folding what results in insulin full activity. This newly discovered feature of the cytokine MIF could be potentially important for commercially produced insulin, for increasing its stability and/or bioavailability.
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Bloom J, Al-Abed Y. MIF: mood improving/inhibiting factor? J Neuroinflammation 2014; 11:11. [PMID: 24447830 PMCID: PMC3901340 DOI: 10.1186/1742-2094-11-11] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 01/07/2014] [Indexed: 01/09/2023] Open
Abstract
Although major depressive disorder imposes a serious public health burden and affects nearly one in six individuals in developed countries over their lifetimes, there is still no consensus on its pathophysiology. Inflammation and cytokines have emerged as a promising new avenue in depression research, and, in particular, macrophage migration inhibitory factor (MIF) has been shown to be significant in depression physiology. In this review we summarize current research on MIF and depression. We highlight the arguments for MIF as a pro- and antidepressant species and discuss the potential implications for therapeutics.
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Affiliation(s)
- Joshua Bloom
- Hofstra North Shore-LIJ School of Medicine, Hempstead, NY 11549, USA.
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Neve A, Corrado A, Cantatore FP. Immunomodulatory effects of vitamin D in peripheral blood monocyte-derived macrophages from patients with rheumatoid arthritis. Clin Exp Med 2013; 14:275-83. [PMID: 23824148 DOI: 10.1007/s10238-013-0249-2] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 06/24/2013] [Indexed: 12/18/2022]
Abstract
1,25-Dihydroxyvitamin D (1,25(OH)2D3), the active form of vitamin D, modulates both innate and adaptive immune responses. Emerging epidemiological data has also demonstrated disease-modifying and immunomodulatory effects of vitamin D in a wide range of human autoimmune diseases, including rheumatoid arthritis (RA). To evaluate in vitro effects of 1,25(OH) 2D3 in primary cultures of peripheral blood monocyte-derived macrophages of RA patients, monocyte/macrophages, isolated from peripheral blood mononuclear cells of RA patients and healthy subjects by exploiting their ability to adhere to plastic, were treated with increasing concentrations of 1,25(OH)2D3 for 48 h. TNF-α, IL-1 α, IL-1β, IL-6 and RANKL production was determined by ELISA and nitric oxide (NO) release using the Griess method. Immunocytochemistry analysis was also performed to evaluate alterations in transmembrane TNF-α expression after 1,25(OH) 2D3 treatment. A significant dose-dependent decrease in TNF-α and RANKL production by cultured RA macrophages after 1,25(OH)2D3 treatment was found, whereas a significant reduction in normal cells was observed only at higher concentrations. IL-1 α, IL-1β and IL-6 levels were reduced by 1,25(OH) 2D3 at higher concentrations in all cell populations. TNF-α immunostaining was less intense in treated cells compared with untreated. 1,25(OH) 2D3 significantly reduced NO levels regardless of the concentration used. Vitamin D downregulated proinflammatory mediators in monocyte-derived macrophages, and RA cells appeared more sensitive than normal cells. These effects further provide a rationale for the therapeutic value of vitamin D supplementation in the treatment for RA.
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Affiliation(s)
- Anna Neve
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Ospedale "Col. D'Avanzo", V.le degli Aviatori 1, 71100, Foggia, Italy
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Khalyfa A, Kheirandish-Gozal L, Capdevila OS, Bhattacharjee R, Gozal D. Macrophage migration inhibitory factor gene polymorphisms and plasma levels in children with obstructive sleep apnea. Pediatr Pulmonol 2012; 47:1001-11. [PMID: 22451332 PMCID: PMC3405200 DOI: 10.1002/ppul.22560] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2011] [Accepted: 11/28/2011] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Obstructive sleep apnea (OSA) is associated with increased risk for cardiovascular and metabolic dysfunction in both adults and children. In adults with OSA, serum levels of macrophage migration inhibitory factor (MIF) are elevated. Therefore, we assessed plasma MIF levels and MIF allelic variant frequencies in children with and without OSA (NOSA). METHODS A total of 614 consecutive children ages 5-8 years were recruited. Children were divided into those with OSA and NOSA based on the apnea-hypopnea index (AHI). In addition to lipid profile, hsCRP, and fasting insulin and glucose levels, plasma MIF levels were assayed using ELISA, and 28 single nucleotide polymorphisms (SNPs) covering the region were genotyped. Linkage disequilibrium and haplotype blocks were analyzed using Haploview version 4.2 software. RESULTS Morning plasma MIF levels were increased in children with OSA. Of the 28 SNPs tested, the frequency of rs10433310 minor allele was significantly decreased in OSA. This SNP was also associated with reduced fasting insulin and hsCRP levels in OSA. The minor allele frequency of all other 27 SNPs was similar in OSA and NOSA groups. CONCLUSIONS Childhood OSA is associated with higher plasma MIF, hsCRP, and fasting insulin levels that promote cardiometabolic risk, and the MIF gene SNP rs10433310 may account for some of the variance in such risk.
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Affiliation(s)
- Abdelnaby Khalyfa
- Department of Pediatrics, Comer Children's Hospital, The University of Chicago, Chicago, IL 60637, USA
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Sugiyama M, Takenaga F, Kitani Y, Yamamoto G, Okamoto H, Masaoka T, Araki K, Nagoya H, Mori T. Homozygous and heterozygous GH transgenesis alters fatty acid composition and content in the liver of Amago salmon (Oncorhynchus masou ishikawae). Biol Open 2012; 1:1035-42. [PMID: 23213381 PMCID: PMC3507178 DOI: 10.1242/bio.20121263] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 07/02/2012] [Indexed: 12/20/2022] Open
Abstract
Growth hormone (GH) transgenic Amago (Oncorhynchus masou ishikawae), containing the sockeye GH1 gene fused with metallothionein-B promoter from the same species, were generated and the physiological condition through lipid metabolism compared among homozygous (Tg/Tg) and heterozygous GH transgenic (Tg/+) Amago and the wild type control (+/+). Previously, we have reported that the adipose tissue was generally smaller in GH transgenic fish compared to the control, and that the Δ-6 fatty acyl desaturase gene was down-regulated in the Tg/+ fish. However, fatty acid (FA) compositions have not been measured previously in these fish. In this study we compared the FAs composition and content in the liver using gas chromatography. Eleven kinds of FA were detected. The composition of saturated and monounsaturated fatty acids (SFA and MUFA) such as myristic acid (14:0), palmitoleic acid (16:1n-7), and cis-vaccenic acid (cis-18:1n-7) was significantly (P<0.05) decreased in GH transgenic Amago. On the other hand, the composition of polyunsaturated fatty acids (PUFAs) such as linoleic acid (18:2n-6), arachidonic acid (20:4n-6), and docosapentaenoic acid (22:5n-3) was significantly (P<0.05) increased. Levels of serum glucose and triacylglycerol were significantly (P<0.05) decreased in the GH transgenics compared with +/+ fish. Furthermore, 3′-tag digital gene expression profiling was performed using liver tissues from Tg/Tg and +/+ fish, and showed that Mid1 interacting protein 1 (Mid1ip1), which is an important factor to activate Acetyl-CoA carboxylase (ACC), was down-regulated in Tg/Tg fish, while genes involved in FA catabolism were up-regulated, including long-chain-fatty-acid–CoA ligase 1 (ACSL1) and acyl-coenzyme A oxidase 3 (ACOX3). These data suggest that liver tissue from GH transgenic Amago showed starvation by alteration in glucose and lipid metabolism due to GH overexpression. The decrease of serum glucose suppressed Mid1ip1, and caused a decrease of de novo FA synthesis, resulting in a decrease of SFA and MUFA. This induced expression of ACSL1 and ACOX3 to produce energy through β-oxidation in the GH transgenic Amago.
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Affiliation(s)
- Manabu Sugiyama
- Nihon University College of Bioresource Sciences , Kameino 1866, Fujisawa 252-0880 , Japan
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Molecular and functional characterization of macrophage migration inhibitory factor (MIF) homolog of human from lymphatic filarial parasite Wuchereria bancrofti. Parasitol Res 2012; 111:2035-47. [DOI: 10.1007/s00436-012-3051-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Accepted: 07/16/2012] [Indexed: 12/23/2022]
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Vasconcelos RHT, Montenegro SML, Azevedo EAN, Gomes YM, Morais CNL. Genetic susceptibility to chronic Chagas disease: an overview of single nucleotide polymorphisms of cytokine genes. Cytokine 2012; 59:203-8. [PMID: 22595647 DOI: 10.1016/j.cyto.2012.04.035] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 04/11/2012] [Accepted: 04/23/2012] [Indexed: 01/07/2023]
Abstract
Chagas disease is a parasitic infection that is a significant public health problem in Latin America. The mechanisms responsible for susceptibility to the infection and the mechanisms involved in the development of cardiac and digestive forms of chronic Chagas disease remain poorly understood. However, there is growing evidence that differences in susceptibility in endemic areas may be attributable to host genetic factors. The aim of this overview was to analyze the genetic susceptibility to human Chagas disease, particularly that of single nucleotide polymorphisms of cytokine genes. A review of the literature was conducted on the following databases: PubMed/MEDLINE and Scopus. The search strategy included using the following terms: "Cytokines", "Single Nucleotide Polymorphisms" and "Chagas Disease". After screening 25 citations from the databases, 19 studies were selected for the overview. A critical analysis of the data presented in the articles suggests that genetic susceptibility to Chagas disease and chronic Chagas cardiomyopathy is highly influenced by the complexity of the immune response of the host. Follow-up studies based on other populations where Chagas disease is endemic (with distinct ethnic and genetic backgrounds) need to be conducted. These should use a large sample population so as to establish what cytokine genes are involved in susceptibility to and/or progression of the disease.
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Musil R, Schwarz MJ, Riedel M, Dehning S, Cerovecki A, Spellmann I, Arolt V, Müller N. Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression--no influence of celecoxib treatment. J Affect Disord 2011; 134:217-25. [PMID: 21684012 DOI: 10.1016/j.jad.2011.05.047] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 05/26/2011] [Accepted: 05/26/2011] [Indexed: 12/22/2022]
Abstract
OBJECTIVES The involvement of an immune process in the pathophysiology of major depression disorder (MDD) was substantiated by studies demonstrating elevated levels of proinflammatory cytokines and prostaglandin E(2) (PGE(2)). Cyclooxygenase-2 (COX-2) inhibitors lead to a reduced production of PGE(2) and have been shown to improve depressive symptoms. We investigated the three immune parameters macrophage migration inhibitory factor (MIF), transforming growth factor-β (TGF-β) and soluble CD14 (sCD14) in a randomized, placebo-controlled trial of the COX-2 inhibitor celecoxib as add-on therapy in patients with MDD treated with reboxetine. METHODS Thirty-two patients with depression and 20 healthy controls participated in the study. The patients were treated with reboxetine and celecoxib or placebo. Immune parameters were measured from serum at baseline, after three and five weeks using ELISA. RESULTS Celecoxib as add-on strategy resulted in a significant reduction of Hamilton Depression Scale scores compared to placebo. Depressed patients showed significantly elevated MIF (p < 0.001) and reduced TGF-β (p = 0.006) concentrations at baseline. There was no difference in sCD14-concentrations. There was no difference between the placebo and the celecoxib group and no change over time. LIMITATIONS Limitations of the study are the relatively small sample size and lack of functional assessment of HPA axis in parallel. CONCLUSIONS MIF is a promising new candidate in the neuro-immune interplay that may link depressive symptoms, altered immune state and HPA-axis dysregulation. Reduced levels of TGF-β replicate previous findings and support the importance of this regulatory cytokine in major depressive disorder.
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Affiliation(s)
- R Musil
- Psychiatric Clinic of University Munich, Nussbaumstrasse 7, 80336 Munich, Germany.
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Mahmoudi M, Lynch I, Ejtehadi MR, Monopoli MP, Bombelli FB, Laurent S. Protein-nanoparticle interactions: opportunities and challenges. Chem Rev 2011; 111:5610-37. [PMID: 21688848 DOI: 10.1021/cr100440g] [Citation(s) in RCA: 1010] [Impact Index Per Article: 72.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Dani C, Corsini I, Burchielli S, Cangiamila V, Romagnoli R, Jayonta B, Longini M, Paternostro F, Buonocore G. Natural Surfactant Combined with Beclomethasone Decreases Lung Inflammation in the Preterm Lamb. Respiration 2011; 82:369-76. [DOI: 10.1159/000328928] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 04/29/2011] [Indexed: 11/19/2022] Open
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Das UN. Current and emerging strategies for the treatment and management of systemic lupus erythematosus based on molecular signatures of acute and chronic inflammation. J Inflamm Res 2010; 3:143-70. [PMID: 22096364 PMCID: PMC3218729 DOI: 10.2147/jir.s9425] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Lupus is a chronic, systemic inflammatory condition in which eicosanoids, cytokines, nitric oxide (NO), a deranged immune system, and genetics play a significant role. Our studies revealed that an imbalance in the pro- and antioxidants and NO and an alteration in the metabolism of essential fatty acids exist in lupus. The current strategy of management includes administration of nonsteroidal anti-inflammatory drugs such as hydroxychloroquine and immunosuppressive drugs such as corticosteroids. Investigational drugs include the following: 1) belimumab, a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, also known as B-cell-activation factor of the TNF family; 2) stem cell transplantation; 3) rituximab, a chimeric monoclonal antibody against CD20, which is primarily found on the surface of B-cells and can therefore destroy B-cells; and 4) IL-27, which has potent anti-inflammatory actions. Our studies showed that a regimen of corticosteroids and cyclophosphamide, and methods designed to enhance endothelial NO synthesis and augment antioxidant defenses, led to induction of long-lasting remission of the disease. These results suggest that methods designed to modulate molecular signatures of the disease process and suppress inflammation could be of significant benefit in lupus. Some of these strategies could be vagal nerve stimulation, glucose-insulin infusion, and administration of lipoxins, resolvins, protectins, and nitrolipids by themselves or their stable synthetic analogs that are known to suppress inflammation and help in the resolution and healing of the inflammation-induced damage. These strategies are likely to be useful not only in lupus but also in other conditions, such as rheumatoid arthritis, scleroderma, ischemia-reperfusion injury to the myocardium, ischemic heart disease, and sepsis.
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Affiliation(s)
- Undurti N Das
- Jawaharlal Nehru Technological University, Kakinada, Andhra Pradesh, India; UND Life Sciences, Shaker Heights, OH, USA
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Elevated macrophage migration inhibitory factor (MIF) is associated with depressive symptoms, blunted cortisol reactivity to acute stress, and lowered morning cortisol. Brain Behav Immun 2010; 24:1202-8. [PMID: 20382217 DOI: 10.1016/j.bbi.2010.03.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2009] [Revised: 03/31/2010] [Accepted: 03/31/2010] [Indexed: 11/24/2022] Open
Abstract
Macrophage Migration Inhibitory Factor (MIF) is a proinflammatory cytokine produced by leukocytes and the secretory cells of the HPA axis. Remarkably, glucocorticoids (GC) induce leukocyte MIF secretion, while MIF renders leukocytes insensitive to the anti-inflammatory effects of glucocorticoids. In light of reported associations between dysphoric states, increased inflammatory activity, and reduced GC sensitivity, the current study investigated the association between MIF, loneliness and depressive symptoms. The study further investigated the relation between plasma MIF and markers of HPA function, i.e., diurnal cortisol and the cortisol response to acute stress. Healthy university undergraduates (N=126; 64 women) were invited to participate if their scores on the Beck Depression Inventory or UCLA loneliness scale were in the upper or lower quintile of their peer group. Plasma MIF and salivary cortisol were measured in response to a public speaking task. Ambulatory diurnal cortisol was assessed for 5 consecutive days. MIF levels were 40% higher in the high-depressive symptoms group compared to the low depressive symptoms group. Elevated MIF was also associated with a smaller cortisol response to acute stress and lower diurnal morning cortisol values. The observed association between HPA function and MIF remained robust after adjustment for depressive symptoms, and demographic, anthropomorphic, and behavioural factors. High levels of depressive symptoms were likewise associated with lower morning cortisol, but this association became non-significant after adjustment for MIF. MIF may be an important neuro-immune mediator linking depressive symptoms with inflammation and HPA dysregulation.
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Macrophage migration inhibitory factor expression and MIF gene -173 G/C polymorphism in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2010; 22:192-8. [PMID: 19829123 DOI: 10.1097/meg.0b013e328331a596] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIM To investigate the macrophage migration inhibitory factor (MIF) expression and -173 G/C polymorphism of the MIF gene in nonalcoholic fatty liver disease (NAFLD). METHOD Ninety-one patients with diagnosis of NAFLD and 104 healthy controls were included in the study. MIF -173 G/C polymorphism was detected using the PCR-restriction fragment length polymorphism based method. NAFLD was stratified as nonalcoholic steatohepatitis (NASH), probable NASH and steatosis, respectively in groups 1, 2 and 3, according to NAFLD Activity Score. MIF expression was detected by immunohistochemistry staining. RESULTS Mean age of the patients was 50.1+/-9.6 years, and 54 of them were male. Serum alanine aminotransferase and aspartate aminotransferase were 50/83, 42/63 and 31/32, respectively in groups 1, 2 and 3, (P<0.05). Both the MIF expression of hepatocytes and mononuclear cells were more prominent in groups 1 and 2 than group 3. There was no correlation between MIF expression of hepatocytes and fibrosis stage. However, MIF expression of mononuclear cells significantly increased according to fibrosis stage (P<0.05, R : 0.2). There was no significant correlation between MIF genotype and MIF expression in the liver. CONCLUSION MIF expression is significantly increased especially by mononuclear cells in liver tissue of patients with NASH secondary to inflammation. Thus, it should be considered as a consequence not a causal factor.
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Torres OA, Calzada JE, Beraún Y, Morillo CA, González CI, González A, Martín J. Association of the macrophage migration inhibitory factor -173G/C polymorphism with Chagas disease. Hum Immunol 2009; 70:543-6. [PMID: 19376177 DOI: 10.1016/j.humimm.2009.04.022] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 04/02/2009] [Accepted: 04/10/2009] [Indexed: 01/25/2023]
Abstract
Our aim was to evaluate the association of functional polymorphism of macrophage migration inhibitory factor (MIF) gene with Chagas disease. Our study includes two independent cohorts: 240 chagasic patients and 199 controls from Colombia; and 74 chagasic patients and 85 controls from Peru. The single nucleotide polymorphism (SNP) -173 G/C of MIF gene was determined using a polymerase chain reaction (PCR) system with pre-developed TaqMan assay. We observed a statistically significant difference in the distribution of -173*C allele of MIF gene between patients and controls in the Colombian cohort (OR = 1.6, 95% CI = 1.12-2.18, p = 0.006). Similar association was found in the Peruvian cohort (OR = 2.4, 95% CI = 1.31-4.38, p = 0.003). A meta-analysis of the Colombian and Peruvian cohorts demonstrated that the -173 C allele confers a risk effect in chagasic patients (pooled OR = 1.75, 95% CI = 1.30-2.33, p = 0.0002). In addition, a gene dose of the MIF -173 C allele was observed (pooled OR = 4.01, 95% CI = 1.25-12.85, p = 0.004). Our results suggest that the MIF -173G/C polymorphism confers susceptibility to Chagas disease in the populations under study.
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Affiliation(s)
- Orlando A Torres
- Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain
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Cho ML, Moon YM, Heo YJ, Woo YJ, Ju JH, Park KS, Kim SI, Park SH, Kim HY, Min JK. NF-κB inhibition leads to increased synthesis and secretion of MIF in human CD4+ T cells. Immunol Lett 2009; 123:21-30. [DOI: 10.1016/j.imlet.2009.01.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Revised: 01/19/2009] [Accepted: 01/25/2009] [Indexed: 10/21/2022]
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Pearce BD, Garvin SE, Grove J, Bonney EA, Dudley DJ, Schendel DE, Thorsen P. Serum macrophage migration inhibitory factor in the prediction of preterm delivery. Am J Obstet Gynecol 2008; 199:46.e1-6. [PMID: 18241824 DOI: 10.1016/j.ajog.2007.11.066] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Revised: 10/02/2007] [Accepted: 11/27/2007] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Macrophage migration inhibitory factor is a soluble mediator that helps govern the interaction between cytokines and stress hormones (eg, cortisol). We determined whether maternal macrophage migration inhibitory factor levels predicted subsequent preterm delivery. STUDY DESIGN A nested case-control study measuring serum macrophage migration inhibitory factor concentration at 9-23 weeks' gestation in women who ultimately delivered preterm (n = 60) compared with control women who delivered at term (n = 122). We also examined the connection of macrophage migration inhibitory factor with self-reported psychosocial variables. RESULTS Macrophage migration inhibitory factor was elevated in the preterm delivery cases (P = .0004), and log macrophage migration inhibitory factor concentration showed a graded response relationship with likelihood of preterm delivery. High-macrophage migration inhibitory factor was also associated with maternal risk-taking behavior, which itself was a risk factor for preterm delivery. Macrophage migration inhibitory factor remained associated independently with preterm delivery after adjusting regression models for several other preterm delivery risk factors (odds ratio, 3.11, 95% confidence interval, 1.54-6.30). CONCLUSION High-serum macrophage migration inhibitory concentration in early to midpregnancy is linked with subsequent preterm delivery.
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Affiliation(s)
- Brad D Pearce
- Department of Psychology, Emory University, Atlanta, GA 30332, USA.
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Sharma A, Bhattacharya B, Puri RK, Maheshwari RK. Venezuelan equine encephalitis virus infection causes modulation of inflammatory and immune response genes in mouse brain. BMC Genomics 2008; 9:289. [PMID: 18558011 PMCID: PMC2440554 DOI: 10.1186/1471-2164-9-289] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2007] [Accepted: 06/16/2008] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Neurovirulent Venezuelan equine encephalitis virus (VEEV) causes lethal encephalitis in equines and is transmitted to humans by mosquitoes. VEEV is highly infectious when transmitted by aerosol and has been developed as a bio-warfare agent, making it an important pathogen to study from a military and civilian standpoint. Molecular mechanisms of VEE pathogenesis are poorly understood. To study these, the gene expression profile of VEEV infected mouse brains was investigated. Changes in gene expression were correlated with histological changes in the brain. In addition, a molecular framework of changes in gene expression associated with progression of the disease was studied. RESULTS Our results demonstrate that genes related to important immune pathways such as antigen presentation, inflammation, apoptosis and response to virus (Cxcl10, CxCl11, Ccl5, Ifr7, Ifi27 Oas1b, Fcerg1,Mif, Clusterin and MHC class II) were upregulated as a result of virus infection. The number of over-expressed genes (>1.5-fold level) increased as the disease progressed (from 197, 296, 400, to 1086 at 24, 48, 72 and 96 hours post infection, respectively). CONCLUSION Identification of differentially expressed genes in brain will help in the understanding of VEEV-induced pathogenesis and selection of biomarkers for diagnosis and targeted therapy of VEEV-induced neurodegeneration.
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Affiliation(s)
- Anuj Sharma
- Centre for Combat Casualty and Life Sustainment Research, Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
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35
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Vera PL, Wang X, Meyer-Siegler KL. Upregulation of macrophage migration inhibitory factor (MIF) and CD74, receptor for MIF, in rat bladder during persistent cyclophosphamide-induced inflammation. Exp Biol Med (Maywood) 2008; 233:620-6. [PMID: 18375833 DOI: 10.3181/0709-rm-240] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The objective of this study was to determine if macrophage migration inhibitory factor (MIF) is upregulated in the bladder during persistent cystitis. MIF is a pro-inflammatory cytokine found pre-formed in the urothelium. Previous findings showed that acute bladder inflammation increased MIF release into the bladder lumen while upregulating MIF and CD74 (MIF receptor) in the bladder. Because the effects of persistent cystitis on MIF and CD74 are not known, MIF and CD74 changes in the bladder were examined after short-term (1-day) or persistent (8-day) cyclophosphamide (CYP)-induced bladder inflammation. Anesthetized male Sprague-Dawley rats received either a single CYP treatment (150 mg/kg, ip; saline, control) and examined 1 day after treatment (short-term), or repeated CYP doses (20-75 mg/ kg, ip; saline, control; every third day for 8 days) and examined after 8 days of treatment (persistent). MIF protein levels in urine and bladder were determined. In addition, Mif, CD74, and cox-2 expression in the bladder was determined. Histology verified cystitis and MIF and CD74 immunoreactivity in the bladder. Repeated CYP doses were decreased to avoid toxicity. Short-term or repeated low CYP doses (40 mg/kg; 8 days) increased urinary MIF and decreased bladder MIF amounts while upregulating bladder Mif and CD74 mRNA expression. Persistent CYP-induced bladder inflammation (even at 40 mg/kg; 8-day treatment) also upregulated other inflammatory cytokines (CCL5, IL-11, iNOS) in the bladder. Short-term and persistent (low dose) CYP cystitis are associated with markedly increased MIF release into the urine and upregulation of Mif and CD74 in bladder. This supports the hypothesis that MIF and CD74 play a significant role in both acute and persistent stages of bladder inflammation.
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Affiliation(s)
- Pedro L Vera
- Bay Pines VA Healthcare System, Research & Development (151), 10000 Bay Pines Boulevard, Bay Pines, FL 33744, USA.
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Herder C, Klopp N, Baumert J, Müller M, Khuseyinova N, Meisinger C, Martin S, Illig T, Koenig W, Thorand B. Effect of macrophage migration inhibitory factor (MIF) gene variants and MIF serum concentrations on the risk of type 2 diabetes: results from the MONICA/KORA Augsburg Case-Cohort Study, 1984-2002. Diabetologia 2008; 51:276-84. [PMID: 17712545 DOI: 10.1007/s00125-007-0800-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2007] [Accepted: 07/19/2007] [Indexed: 10/22/2022]
Abstract
AIMS/HYPOTHESIS Macrophage migration inhibitory factor (MIF) is a central mediator of innate immunity. Our aim was to investigate the triangular association between MIF genotypes, circulating MIF concentrations and incident type 2 diabetes, and to use a Mendelian randomisation approach to assess the causal role of MIF. METHODS Using a case-cohort design within the population-based MONICA/KORA Augsburg Study, based on 502 individuals with incident type 2 diabetes (293 men, 209 women) and 1,632 non-cases (859 men, 773 women), we determined MIF serum levels at baseline and genotyped four MIF single nucleotide polymorphisms (SNPs). RESULTS The C allele of SNP rs1007888 (3.8 kb 3' of the translation termination codon) was associated with increased circulating MIF. MIF genotype rs1007888CC was associated with an increased risk of type 2 diabetes in women [hazard ratio (95% CI) 1.74 (1.02-2.97)], but not in men [1.17 (0.75-1.81)]. Elevated MIF serum levels were associated with higher type 2 diabetes risk also only in women [HR (95% CI) 1.95 (1.15-3.29) comparing extreme quartiles after multiple adjustment], but not in men (p for interaction 0.039). The association between MIF levels and incident type 2 diabetes was significantly higher in obese women (111 cases, 147 non-cases) compared with non-obese women (98 cases, 626 non-cases; p for BMI interaction 0.0002). CONCLUSIONS/INTERPRETATION The consistent triangular relationship between genotypes, serum levels and incident type 2 diabetes in women indicates that MIF may play a causal role in the aetiology of type 2 diabetes and that elevated MIF levels confer a higher disease risk.
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Affiliation(s)
- C Herder
- Institute for Clinical Diabetes Research, German Diabetes Centre, Leibniz Centre at Heinrich Heine University, Dusseldorf, Germany
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Onodera S, Oshima S, Nishihira J, Yasuda K, Tohyama H, Irie K, Koyama Y. Active immunization against macrophage migration inhibitory factor using a novel DNA vaccine prevents ovariectomy-induced bone loss in mice. Vaccine 2008; 26:829-36. [DOI: 10.1016/j.vaccine.2007.11.066] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2007] [Revised: 10/31/2007] [Accepted: 11/22/2007] [Indexed: 10/22/2022]
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Thomas W, Seidenspinner S, Kawczyńska-Leda N, Kramer BW, Chmielnicka-Kopaczyk M, Marx A, Szymankiewicz M, Speer CP. Systemic fetal inflammation and reduced concentrations of macrophage migration inhibitory factor in tracheobronchial aspirate fluid of extremely premature infants. Am J Obstet Gynecol 2008; 198:64.e1-6. [PMID: 18166309 DOI: 10.1016/j.ajog.2007.06.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2006] [Revised: 03/23/2007] [Accepted: 06/07/2007] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Macrophage migration inhibitory factor is a proinflammatory mediator of innate immunity, enhances cell growth, and plays a role in preterm delivery. We speculated that funisitis, reflecting fetal systemic inflammation, would be associated with higher concentrations of macrophage migration inhibitory factor in airways of extremely premature infants. STUDY DESIGN We measured macrophage migration inhibitory factor by enzyme linked immunosorbent assay in tracheobronchial aspirate fluid of 35 ventilated infants less than 30 weeks' gestational age, throughout the first week of life. Three groups were distinguished histologically: chorioamnionitis, funisitis, and control. RESULTS Unexpectedly, funisitis was associated with significantly decreased macrophage migration inhibitory factor in tracheobronchial aspirate fluid on day 1 (P < .01) and levels remained lower than in the chorioamnionitis group thereafter. For the 35 patients in total, macrophage migration inhibitory factor steadily declined. CONCLUSION Decreased macrophage migration inhibitory factor concentrations in airways of extremely premature infants with systemic fetal inflammation early in life might predispose them to pulmonary infection and interfere with maturation of the lung, contributing to adverse pulmonary outcome.
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Affiliation(s)
- Wolfgang Thomas
- University Children's Hospital, University of Würzburg, Würzburg, Germany
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Tao W, Mallard B. Differentially expressed genes associated with Staphylococcus aureus mastitis of Canadian Holstein cows. Vet Immunol Immunopathol 2007; 120:201-11. [PMID: 17658619 DOI: 10.1016/j.vetimm.2007.06.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2007] [Revised: 06/08/2007] [Accepted: 06/14/2007] [Indexed: 10/23/2022]
Abstract
To study pathway specific gene expression within the immune-endocrine axis of dairy cows with Staphylococcus aureus mastitis, mRNA was collected from blood mononuclear cells (BMCs) and milk somatic cells (MSCs) of cows (n=7) identified as culture positive for S. aureus and their matched negative control cows (n=7) with no evidence of S. aureus mastitis. Labeled cDNA probes derived from BMCs and MSCs of infected and healthy cows were applied to a bovine immune-endocrine cDNA array containing 167 genes. Genes with a log(2) ratio> or =0.5 were considered to be up-regulated and genes with a log(2) ratio< or =-0.5 to be down-regulated. In total, 22 genes were differentially displayed in BMCs and 16 genes in MSCs of case versus controls. Expression of selected genes in BMCs and MSCs were confirmed by real-time PCR. The RT-PCR results were highly correlated with microarray measurements. Some of these genes, such as interleukin (IL)-8 have been previously implicated in other bacterial diseases, and are known to regulate immune responses; whereas, others may reflect novel pathways or genes involved in progressive mammary gland disease. For example, IL-18 was up-regulated in BMCs but not MSCs of mastitic quarters, while IL-17 was more highly expressed in MSCs compared to BMCs. This study identified a number of differentially expressed genes associated with bovine S. aureus mastitis and demonstrates the intricacy of the patterns of gene expression that influence host response to a complex pathogen of significant relevance to both human and veterinary medicine.
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Affiliation(s)
- Wenjing Tao
- Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada N1G 2W1
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40
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Suttmann H, Riemensberger J, Bentien G, Schmaltz D, Stöckle M, Jocham D, Böhle A, Brandau S. Neutrophil granulocytes are required for effective Bacillus Calmette-Guérin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res 2007; 66:8250-7. [PMID: 16912205 DOI: 10.1158/0008-5472.can-06-1416] [Citation(s) in RCA: 150] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The role of polymorphonuclear neutrophil granulocytes (PMN) in antitumoral immune responses displays a striking dichotomy. Under inflammatory conditions, PMN may promote tumor growth and progression. In contrast, especially in the context of therapeutic interventions, PMN can exert important antitumor functions. However, until now, the mechanisms of PMN-mediated activation of tumor immunity are poorly defined. Based on a murine model of Bacillus Calmette-Guérin (BCG) immunotherapy of bladder cancer, we provide evidence for a novel immunoregulatory role of this leukocyte subset. PMN immigrate into the bladder after intravesical BCG instillation and depletion of PMN from tumor-bearing mice completely abrogated antitumor efficacy of BCG. PMN stimulated with BCG in vitro as well as PMN isolated from the urine of BCG-treated patients were a major source of the chemokines interleukin-8, growth-related oncogene-alpha, macrophage inflammatory protein-1 alpha and of the inflammatory cytokine migration inhibitory factor. In vitro, BCG-stimulated PMN indirectly induced T-cell chemotaxis via the accessory function of activated monocytes. In vivo, depletion of PMN from BCG-treated mice significantly impaired CD4(+) T-cell trafficking to the bladder. These data show that PMN direct the migration of effector cells to the bladder and by this means are indispensable for effective tumor immunotherapy. Thus, our findings provide evidence for a novel early immunoregulatory role of these innate immune cells in local antitumor immunity.
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Affiliation(s)
- Henrik Suttmann
- Division of Immunotherapy, Research Center Borstel, Borstel, Germany
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Smith LL, McKune AJ, Semple SJ, Sibanda E, Steel H, Anderson R. Changes in serum cytokines after repeated bouts of downhill running. Appl Physiol Nutr Metab 2007; 32:233-40. [PMID: 17486164 DOI: 10.1139/h06-106] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The purpose of this study was to examine changes in serum cytokines after repeated bouts of aerobically biased eccentric exercise. Six untrained males ran down a -13.5% treadmill grade for 60 min on two occasions (RUN1 and RUN2) at a speed equal to 75% of their VO2 peak on a level grade; runs were spaced 14 d apart. Serum was collected before, after, and every hour for 12 h, and every 24 h for 6 d. Cytokines were assessed using 17 multiplex bead technology (Bio-Rad). Creatine kinase (CK) and delayed-onset muscle soreness (DOMS) were assessed before and 24-120 h after. Results were analyzed using a repeated measures analysis of variance (p <or= 0.05). All comparisons were between RUN1 and RUN2. CK and DOMS were significantly elevated after RUN1 compared with RUN2, indicative of a repeated bout effect. Regarding cytokines, during the initial 12 h period after RUN2, there was a 50% decrease in pro-inflammatory interleukin-6 (IL-6), a 10% decrease in pro-inflammatory macrophage chemotactic protein-1, and a 95% elevation in anti-inflammatory interleukin-10 (IL-10). Regarding 24 h periods, after RUN2 there was an 8% reduction in pro-inflammatory interleukin-8 (IL-8). However, pro-inflammatory macrophage inflammatory factor-1beta (MIF-1beta) was 18% higher during the 12 h after RUN2. The overall cytokine profile suggests a slight reduction in systemic inflammation after RUN2.
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Affiliation(s)
- Lucille L Smith
- Department of Sport and Physical Rehabilitation Sciences, Tshwane University of Technology, Pretoria 0001, South Africa.
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de Prada TP, Pozzi AO, Coronado MT, Pounchard MA, Gonzalez P, Boscá L, Fantidis P. Atherogenesis takes place in cholesterol-fed rabbits when circulating concentrations of endogenous cortisol are increased and inflammation suppressed. Atherosclerosis 2007; 191:333-339. [PMID: 16806229 DOI: 10.1016/j.atherosclerosis.2006.05.049] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2006] [Revised: 05/18/2006] [Accepted: 05/24/2006] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is an inflammatory disease, but the response of the endogenous anti-inflammatory system during this process has not been evaluated previously. Cortisol is the end product of this anti-inflammatory system, but is also able to activate cellular processes that induce atherogenesis; however, it is unknown whether atherogenesis occurs when circulating concentrations of endogenous cortisol are increased or when they are decreased. We have evaluated the counter-regulatory responses of cortisol and interleukin-1beta (IL-1beta) during the short- and long-term responses to vascular injury in rabbits fed a 2% cholesterol diet. In the short-term group (n=18), serum cortisol and IL-1beta concentrations were measured after 10, 20 and 30 days. Rabbits developed hypercholesterolemia and hypercortisolemia, with only modest increases in IL-1beta. Although inflammation was low-grade, atherogenesis took place, with subintimal lipid accumulation evident on day 30. In the second group (n=18), we evaluated variables after 40, 60 and 90 days. This group developed hypercholesterolemia, but serum cortisol concentrations were inappropriately normal, while IL-1beta concentrations were elevated 8.6-fold; advanced atherosclerotic plaques were evident on days 60 and 90. These results show that atherogenesis occurs when high endogenous cortisol levels are suppressing inflammation, and are consistent with a promotion of early atherogenesis by high cortisol concentrations.
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Affiliation(s)
- Teresa Pérez de Prada
- Laboratory of Experimental Cardiology, Medicina y Cirugía Experimentales, Hospital Clínico San Carlos, Madrid, Spain
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Meyer-Siegler KL, Iczkowski KA, Leng L, Bucala R, Vera PL. Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. THE JOURNAL OF IMMUNOLOGY 2007; 177:8730-9. [PMID: 17142775 DOI: 10.4049/jimmunol.177.12.8730] [Citation(s) in RCA: 196] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is overexpressed in prostate cancer, but the mechanism by which MIF exerts effects on tumor cells remains undetermined. MIF interacts with its identified membrane receptor, CD74, in association with CD44, resulting in ERK 1/2 activation. Therefore, we hypothesized that increased expression or surface localization of CD74 and MIF overexpression by prostate cancer cells regulated tumor cell viability. Prostate cancer cell lines (LNCaP and DU-145) had increased MIF gene expression and protein levels compared with normal human prostate or benign prostate epithelial cells (p < 0.01). Although MIF, CD74, and CD44 variant 9 expression were increased in both androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells, cell surface of CD74 was only detected in androgen-independent (DU-145) prostate cancer cells. Therefore, treatments aimed at blocking CD74 and/or MIF (e.g., inhibition of MIF or CD74 expression by RNA interference or treatment with anti-MIF- or anti-CD74- neutralizing Abs or MIF-specific inhibitor, ISO-1) were only effective in androgen-independent prostate cancer cells (DU-145), resulting in decreased cell proliferation, MIF protein secretion, and invasion. In DU-145 xenografts, ISO-1 significantly decreased tumor volume and tumor angiogenesis. Our results showed greater cell surface CD74 in DU-145 prostate cancer cells that bind to MIF and, thus, mediate MIF-activated signal transduction. DU-145 prostate cancer cell growth and invasion required MIF activated signal transduction pathways that were not necessary for growth or viability of androgen-dependent prostate cells. Thus, blocking MIF either at the ligand (MIF) or receptor (CD74) may provide new, targeted specific therapies for androgen-independent prostate cancer.
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Affiliation(s)
- Katherine L Meyer-Siegler
- Research and Development (151), The Bay Pines Veterans Affairs Healthcare System, 10000 Bay Pines Boulevard, Bay Pines, FL 33744, USA.
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Dambacher J, Staudinger T, Seiderer J, Sisic Z, Schnitzler F, Pfennig S, Hofbauer K, Konrad A, Tillack C, Otte JM, Diebold J, Göke B, Ochsenkühn T, Lohse P, Brand S. Macrophage migration inhibitory factor (MIF) -173G/C promoter polymorphism influences upper gastrointestinal tract involvement and disease activity in patients with Crohn's disease. Inflamm Bowel Dis 2007; 13:71-82. [PMID: 17206642 DOI: 10.1002/ibd.20008] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with increased expression in inflammatory bowel disease. The aim of the study was to analyze the role of the MIF -173G/C single nucleotide polymorphism in Crohn's disease (CD). METHODS Using restriction fragment length polymorphism analysis, genomic DNA of 198 patients with CD and 159 unrelated controls was analyzed for the -173G/C SNP in the MIF promoter region. Colonic MIF mRNA expression was measured by quantitative polymerase chain reaction (PCR), serum MIF levels by enzyme-linked immunosorbent assay (ELISA). RESULTS Thirty-six of the 146 G/G wildtype carriers (24.7%) but only 3 of the 45 G/C heterozygotes (6.7%) and only 1 of the C/C homozygotes (14.3%) were diagnosed with upper gastrointestinal tract involvement (P = 0.009, odds ratio [OR] = 0.22, 95% confidence interval [CI], 0.06-0.75 for wildtype versus hetero- and homozygous carriers). This result was confirmed in a second prospective study, in which all patients diagnosed with upper gastrointestinal involvement (n = 13) were G/G wildtype carriers (P = 0.01 versus controls). All patients (n = 12; 100%) with a Crohn's disease activity index (CDAI) > 300 were G/G wildtype carriers compared to only 65.6% wildtype carriers in the group with a CDAI < 150 (P = 0.016). MIF is expressed in the colonic mucosa of CD patients and intestinal epithelial cells but its mRNA expression does not correlate with the degree of inflammation and is not upregulated by proinflammatory cytokines. In CD, MIF serum levels are not influenced by the MIF -173G/C polymorphism. CONCLUSIONS The MIF -173G/C polymorphism appears to be a factor contributing to a particular CD phenotype characterized by protection against upper gastrointestinal tract involvement and severe disease activity.
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Affiliation(s)
- Julia Dambacher
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
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Affiliation(s)
- Amit Maity
- Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Wu XY, Pan H, Huang P, Wu B, Jiang HJ, Mei L. Dinitrochlorobenzene-induced colitis and its correlations with neurogenic inflammation of gut in rats. Shijie Huaren Xiaohua Zazhi 2006; 14:2067-2072. [DOI: 10.11569/wcjd.v14.i21.2067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the immune mechanism of ulcerative colitis as well as the relationship between ulcerative colitis and enteric nervous system.
METHODS: Male Sprague Dawley rats were divided into 2, 4-dinitrochlorobenzene (DNCB) groups and ethanol (control) group. After sensitized by DNCB smeared on the abdominal skin, the rats were challenged with DNCB by enema or intrathecal injection. The weight, stool viscosity and hematochezia were observed and accumulated as the disease active index (DAI) score; the colon pathological score was achieved by macropathology and HE staining of section prepared for microscopy; and the activity of leukocyte migration inhibitory factor (LMIF) was determined by immunofluorescence staining in colon tissues.
RESULTS: In the rats treated with 4 and 8 g/L DNCB enema, the macropathological and microscopic scores were significantly higher than those in the controls (macropathological: 2.200 ± 0.416, 3.857 ± 0.143 vs 0.143 ± 0.143, P < 0.05; microscopic: 2.000 ± 0.471, 3.714 ± 0.184 vs 0.429 ± 0.297, P < 0.05). The colon tissue showed higher fluorescence intensity of LMIF in the rats treated with DNCB enema than that in the controls. In the rats intrathecally injected with 8 and 16 g/L DNCB, the DAI scores were significantly higher than those in the control rats (P < 0.05 and P <0.01). Colon HE staining showed mucosal edema in the rats intrathecally injected 4 g/L DNCB, infiltration of numerous inflammatory cells in those with 8 g/L DNCB, and mucosal erosion, necrosis, and ulceration in those with 16 g/L DNCB.
CONCLUSION: Colitis can be induced by DNCB enema or intrathecal injection in sensitized rat, which reflects a delayed type of hypersensitivity (DTH). The enteric nervous system and neuroimmune mediator LMIF play important roles in the DNCB-induced colitis.
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Baugh JA, Gantier M, Li L, Byrne A, Buckley A, Donnelly SC. Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1. Biochem Biophys Res Commun 2006; 347:895-903. [PMID: 16854377 DOI: 10.1016/j.bbrc.2006.06.148] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2006] [Accepted: 06/25/2006] [Indexed: 11/27/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.
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Affiliation(s)
- John A Baugh
- School of Medicine and Medical Science, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
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Uchino BN. Social Support and Health: A Review of Physiological Processes Potentially Underlying Links to Disease Outcomes. J Behav Med 2006; 29:377-87. [PMID: 16758315 DOI: 10.1007/s10865-006-9056-5] [Citation(s) in RCA: 1282] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2006] [Indexed: 10/24/2022]
Abstract
Social support has been reliably related to lower rates of morbidity and mortality. An important issue concerns the physiological mechanisms by which support influences such health endpoints. In this review, I examine evidence linking social support to changes in cardiovascular, neuroendocrine, and immune function. Consistent with epidemiological evidence, social support appears to be related to more positive "biological profiles" across these disease-relevant systems. Recent research on immune-mediated inflammatory processes is also starting to provide data on more integrative physiological mechanisms potentially linking social support to health. The implications of these links, along with future research directions are discussed.
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Affiliation(s)
- Bert N Uchino
- Department of Psychology and Health Psychology Program, University of Utah, 380 S. 1530 E., Rm. 502, Salt Lake City, 84112 Utah, USA.
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Abstract
As potential applications of nanotechnology and nanoparticles increase, so too does the likelihood of human exposure to nanoparticles. Because of their small size, nanoparticles are easily taken up into cells (by receptor-mediated endocytosis), whereupon they have essentially free access to all cellular compartments. Similarly to macroscopic biomaterial surfaces (that is, implants), nanoparticles become coated with a layer of adsorbed proteins immediately upon contact with physiological solutions (unless special efforts are taken to prevent this). The process of adsorption often results in conformational changes of the adsorbed protein, which may be affected by the larger curvature of nanoparticles compared with implant surfaces. Protein adsorption may result in the exposure at the surface of amino acid residues that are normally buried in the core of the native protein, which are recognized by the cells as "cryptic epitopes." These cryptic epitopes may trigger inappropriate cellular signaling events (as opposed to being rejected by the cells as foreign bodies). However, identification of such surface-exposed epitopes is nontrivial, and the molecular nature of the adsorbed proteins should be investigated using biological and physical science methods in parallel with systems biology studies of the induced alterations in cell signaling.
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Affiliation(s)
- Iseult Lynch
- Irish Centre for Colloid Science and Biomaterials, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
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Todros T, Bontempo S, Piccoli E, Ietta F, Romagnoli R, Biolcati M, Castellucci M, Paulesu L. Increased levels of macrophage migration inhibitory factor (MIF) in preeclampsia. Eur J Obstet Gynecol Reprod Biol 2006; 123:162-6. [PMID: 15894418 DOI: 10.1016/j.ejogrb.2005.03.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2004] [Revised: 02/23/2005] [Accepted: 03/16/2005] [Indexed: 10/25/2022]
Abstract
OBJECTIVE MIF is a proinflammatory cytokine involved in reproduction. Systemic activation of maternal inflammatory cell responses may play an important role in the pathogenesis of preeclampsia (PE). We hypothesized that MIF could be involved in preeclampsia. STUDY DESIGN Concentration of immunoreactive MIF was assayed by enzyme-linked immunoassorbent assay (ELISA) in maternal serum samples obtained from 41 term control pregnancies and 21 severe preeclamptic pregnancies (14 delivered before and 7 at or after 34 weeks). RESULTS MIF serum levels were significantly higher in preeclamptic pregnancies (median 12.74 ng/ml) than in control group (median 5.3n g/ml) p = 0.001. MIF concentration was significantly higher when delivery occurred <34 weeks (median 17.80 ng/ml; range 2.80-80.20) than in the group delivered > or = 34 weeks (median 6.16 ng/ml; range 1.62-23.65) p = 0.037. CONCLUSIONS High maternal serum levels MIF in pregnancies complicated by severe preeclampsia strongly support the role of inflammation in the pathogenesis of this disease.
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Affiliation(s)
- Tullia Todros
- Department of Obstetrics and Gynecology, University of Turin, Via Ventimiglia, 3, 10126 Turin, Italy.
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