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Liao H, Yang J, Xu Y, Xie J, Li K, Chen K, Pei J, Luo Q, Pan M. Mannose-Binding Lectin 2 as a Potential Therapeutic Target for Hepatocellular Carcinoma: Multi-Omics Analysis and Experimental Validation. Cancers (Basel) 2023; 15:4900. [PMID: 37835594 PMCID: PMC10571644 DOI: 10.3390/cancers15194900] [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: 07/23/2023] [Revised: 09/28/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
Mannose-binding lectin 2 (MBL2), a member of the multimeric lectin family, is crucial in immune regulation and tumor development. MBL2 gene polymorphisms are associated with the risk and prognosis of various tumors, including hepatocellular carcinoma (HCC). Its functional role in HCC remains largely unclear. In this study, we aimed to identify whether MBL2 is a key regulator and a potential therapeutic target for HCC. A bioinformatics analysis revealed close relationships among MBL2 downregulation, the tumor-associated proliferation and metastasis pathway, and tumor immunosuppressive microenvironments. Lower expression of MBL2 in HCC patients was linked to an unfavorable prognosis. A cell counting kit-8 assay, colony formation assay, transwell migration assay, and wound healing assay further confirmed that the overexpression of MBL2 could directly inhibit the proliferation and metastasis of HCC. Moreover, MBL2 expression was regulated by miR-34c-3p, as confirmed by the dual-luciferase reporter assay, thereby demonstrating tumor progression in HCC cells. Thus, our study offers the first comprehensive confirmation of the role of MBL2 in the development of HCC through multi-omics analysis and experimental validation. Furthermore, miR-34c-3p was found to be an upstream mechanism of the downregulation of MBL2 expression and could be a promising therapeutic target, expanding treatment options for patients with HCC.
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Affiliation(s)
- Hangyu Liao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Jun Yang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Yuyan Xu
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Juncheng Xie
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Ke Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
- Department of General Surgery, The First Hospital of Changsha, Changsha 410000, China
| | - Kunling Chen
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Jingyuan Pei
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Qiong Luo
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
- Department of General Surgery, Affiliated Hengyang Hospital, Southern Medical University (Hengyang Central Hospital), Hengyang 421000, China
| | - Mingxin Pan
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
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Kalia N, Singh J, Kaur M. The ambiguous role of mannose-binding lectin (MBL) in human immunity. Open Med (Wars) 2021; 16:299-310. [PMID: 33681468 PMCID: PMC7917369 DOI: 10.1515/med-2021-0239] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 01/22/2021] [Accepted: 01/29/2021] [Indexed: 12/30/2022] Open
Abstract
Mannose-binding lectin (MBL) and lectin complement pathway have become targets of increasing clinical interest. Many aspects of MBL have been recently explored, including the structural properties that allow it to distinguish self from non-self/altered-self structures. Experimental evidences have declared the additional 5′- and 3′-variants that in amalgamation with well-known secretor polymorphisms change MBL function and concentration. Moreover, the current review highlights the differential behavior of MBL on exposure with extra/intracellular pathogens and in autoimmune diseases, stressing the fact that “high MBL levels can increase diseases susceptibility,” a paradox that needs justification. Attributable to these discrepancies, no absolute level of MBL deficiency could be defined so far and thus must be interpreted for specific diseases through case–control population-specific designs. Overall, it is evident that further research is needed about MBL and the lectin pathway of complement. Particularly, the transformative role of MBL over evolution is of interest and its role with regard to pathogenesis of different diseases and potential therapeutic targets within the respective pathways should be further explored. Apart from this, it is necessary to adopt an extensive locus-wide methodology to apprehend the clinical significance of MBL2 polymorphisms in a variety of infectious diseases by the future studies.
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Affiliation(s)
- Namarta Kalia
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, India.,Department of Biological Sciences, George Washington University, Washington, DC 20052, USA
| | - Jatinder Singh
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, India
| | - Manpreet Kaur
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, India
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Jana UK, Suryawanshi RK, Prajapati BP, Kango N. Prebiotic mannooligosaccharides: Synthesis, characterization and bioactive properties. Food Chem 2020; 342:128328. [PMID: 33257024 DOI: 10.1016/j.foodchem.2020.128328] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 08/08/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022]
Abstract
Functional oligosaccharides are non-digestible food ingredients that confer numerous health benefits. Among these, mannooligosaccharides (MOS) are emerging prebiotics that have characteristic potential bio-active properties. Microbial mannanases can be used to break down mannan rich agro-residues to yield MOS. Various applications of MOS as health promoting functional food ingredient may open up newer opportunities in food and feed industry. Enzymatic hydrolysis is the widely preferred method over chemical hydrolysis for MOS production. Presently, commercial MOS is being derived from yeast cell wall mannan and is widely used as prebiotic in feed supplements for poultry and aquaculture. Apart from stimulating the growth of probiotic microflora, MOS impart anticancer and immunomodulatory effects by inducing different gene markers in colon cells. This review summarizes recent developments and future prospects of enzymatic synthesis of MOS from various mannans, their structural characteristics and their potential health benefits.
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Affiliation(s)
- Uttam Kumar Jana
- Department of Microbiology, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, MP 470003, India.
| | - Rahul Kumar Suryawanshi
- Department of Microbiology, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, MP 470003, India.
| | - Bhanu Pratap Prajapati
- Department of Microbiology, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, MP 470003, India.
| | - Naveen Kango
- Department of Microbiology, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, MP 470003, India.
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Beulaja Manikandan S, Manikandan R, Arumugam M, Mullainadhan P. An overview on human serum lectins. Heliyon 2020; 6:e04623. [PMID: 32923708 PMCID: PMC7475231 DOI: 10.1016/j.heliyon.2020.e04623] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/16/2020] [Accepted: 07/31/2020] [Indexed: 01/25/2023] Open
Abstract
An extensive literature survey done on the various naturally occurring lectins in human serum upon its salient features such as methods of detection, level and sites of synthesis, binding specificity, cation dependency, modes of isolation, molecular and functional characterization way back from 1930s to till date was presented in a tabulated section. In addition, the generation of lectin and other immune molecules in vertebrates upon treatment with exogenous elicitors has also been framed in a tabular form. Furthermore, ANEW lectin induced in human serum for the very first time by an exogenous elicitor was detected, isolated and characterized by us whose features are also tabulated explicitly.
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Affiliation(s)
- S. Beulaja Manikandan
- Department of Biochemistry, Annai Veilankanni's College for Women, Saidapet, Chennai, Tamilnadu, 600015, India
| | - R. Manikandan
- Department of Zoology, University of Madras, Guindy Campus, Chennai, Tamilnadu, 600025, India
| | - M. Arumugam
- Department of Zoology, University of Madras, Guindy Campus, Chennai, Tamilnadu, 600025, India
| | - P. Mullainadhan
- Department of Zoology, University of Madras, Guindy Campus, Chennai, Tamilnadu, 600025, India
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Sinha A, Singh V, Tandon R, Mohan Srivastava L. Dichotomy of complement system: Tumorigenesis or destruction. Immunol Lett 2020; 223:89-96. [PMID: 32333965 DOI: 10.1016/j.imlet.2020.04.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 04/06/2020] [Accepted: 04/18/2020] [Indexed: 01/12/2023]
Abstract
Complement system proteins, their regulators and endpoint effector complex significantly promote tumor growth by upregulation of oncogenic growth factors, activation of mitogenic signalling pathways and breakage of normal cell cycle. Contrastingly, complement cascades, initiated by anti-tumor therapeutic antibodies, also play a pivotal role in therapy response. This contradictory role of complement system possibly be a very crucial factor for the outcomes of antibody mediated immunotherapies. Herein, we reviewed the twin role of the complement system in cancer and also the genetic variations in complement system genes. Future studies should be focused on the biomarker discovery for the personalised cancer immunotherapies.
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Affiliation(s)
- Ashima Sinha
- Department of BiochemIstry, Sir Ganga Ram Hospital, New Delhi-110060, India; SAGE Publications India Pvt Ltd., New Delhi-110044, India
| | - Virendra Singh
- Laboratory of Precision Medicine Research, School of Biotechnology, Jawaharlal Nehru University, New Delhi-110067, India.
| | - Ravi Tandon
- Laboratory of AIDS research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi-110067, India
| | - Lalit Mohan Srivastava
- Department of Biochemistry and Lab Medicine, Sir Ganga Ram Kolmet Hospital, New Delhi-110005, India.
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Jana UK, Kango N. Characteristics and bioactive properties of mannooligosaccharides derived from agro-waste mannans. Int J Biol Macromol 2020; 149:931-940. [PMID: 32014482 DOI: 10.1016/j.ijbiomac.2020.01.304] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/28/2020] [Accepted: 01/31/2020] [Indexed: 12/14/2022]
Abstract
Mannooligosaccharides (MOS) were derived using Aspergillus oryzae β-mannanase (ManAo) from different mannan-rich agro-wastes, palm kernel cake (PKC), guar gum and copra meal (CM). Guar gum (GG) released higher amount of MOS (56.31% w/w) from which purification of mannobiose (0.68 mg) and mannotriose (1.26 mg) was demonstrated using size-exclusion chromatography. FTIR analysis of mannan hydrolysates showed characteristic peaks in 1200-900 cm-1 region indicating the presence of MOS. 1H &13C NMR spectra showed presence of anomeric sugar forms of MOS in different mannan hydrolysates. MOS from locust bean gum and guar gum had both α- and β-anomers while PKC and CM had only α-anomer. Growth promotional activities of different MOS were demonstrated using two probiotic Lactobacilli. Besides, enzymatically derived MOS also showed metal (Fe2+) chelating and anti-oxidant activities, wherein best anti-glycating agent was evaluated as MOS from PKC. PKC derived MOS showed highest cytotoxicity (74.19%) against human colon adenocarcinoma cell line (Caco-2). This study demonstrated the prebiotic potential of agro-waste derived MOS and possibility of their utilization as a functional food ingredient.
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Affiliation(s)
- Uttam Kumar Jana
- Department of Microbiology, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar 470003, Madhya Pradesh, India.
| | - Naveen Kango
- Department of Microbiology, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar 470003, Madhya Pradesh, India.
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Di G, Li Y, Zhao X, Wang N, Fu J, Li M, Huang M, You W, Kong X, Ke C. Differential proteomic profiles and characterizations between hyalinocytes and granulocytes in ivory shell Babylonia areolata. FISH & SHELLFISH IMMUNOLOGY 2019; 92:405-420. [PMID: 31212011 DOI: 10.1016/j.fsi.2019.06.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/11/2019] [Accepted: 06/13/2019] [Indexed: 06/09/2023]
Abstract
The haemocytes of the ivory shell, Babylonia areolata are classified by morphologic observation into the following types: hyalinocytes (H) and granulocytes (G). Haemocytes comprise diverse cell types with morphological and functional heterogene and play indispensable roles in immunological homeostasis of invertebrates. In the present study, two types of haemocytes were morphologically identified and separated as H and G by Percoll density gradient centrifugation. The differentially expressed proteins were investigated between H and G using mass spectrometry. The results showed that total quantitative proteins between H and G samples were 1644, the number of up-regulated proteins in G was 215, and the number of down-regulated proteins in G was 378. Among them, cathepsin, p38 MAPK, toll-interacting protein-like and beta-adrenergic receptor kinase 2-like were up-regulated in G; alpha-2-macroglobulin-like protein, C-type lectin, galectin-2-1, galectin-3, β-1,3-glucan-binding protein, ferritin, mega-hemocyanin, mucin-17-like, mucin-5AC-like and catalytic subunit of protein kinase A were down-regulated in G. The results showed that the most significantly enriched KEGG pathways were the pathways related to ribosome, phagosome, endocytosis, carbon metabolism, protein processing in endoplasmic reticulum and oxidative phosphorylation. For phagosome and endocytosis pathway, the number of down-regulation proteins in G was more than that of up-regulation proteins. For lysosome pathway, the number of up-regulation proteins in G was more than that of down-regulation proteins. These results suggested that two sub-population haemocytes perform the different immune functions in B. areolata.
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Affiliation(s)
- Guilan Di
- College of Fisheries, Henan Normal University, Xinxiang, 453007, China
| | - Yanfei Li
- College of Fisheries, Henan Normal University, Xinxiang, 453007, China
| | - Xianliang Zhao
- College of Fisheries, Henan Normal University, Xinxiang, 453007, China
| | - Ning Wang
- College of Fisheries, Henan Normal University, Xinxiang, 453007, China
| | - Jingqiang Fu
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
| | - Min Li
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
| | - Miaoqin Huang
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
| | - Weiwei You
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
| | - Xianghui Kong
- College of Fisheries, Henan Normal University, Xinxiang, 453007, China.
| | - Caihuan Ke
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, China.
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Orsini F, Fumagalli S, Császár E, Tóth K, De Blasio D, Zangari R, Lénárt N, Dénes Á, De Simoni MG. Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α. Arterioscler Thromb Vasc Biol 2019; 38:2678-2690. [PMID: 30354247 PMCID: PMC6221395 DOI: 10.1161/atvbaha.118.311058] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Supplemental Digital Content is available in the text. Objective— Circulating complement factors are activated by tissue damage and contribute to acute brain injury. The deposition of MBL (mannose-binding lectin), one of the initiators of the lectin complement pathway, on the cerebral endothelium activated by ischemia is a major pathogenic event leading to brain injury. The molecular mechanisms through which MBL influences outcome after ischemia are not understood yet. Approach and Results— Here we show that MBL-deficient (MBL−/−) mice subjected to cerebral ischemia display better flow recovery and less plasma extravasation in the brain than wild-type mice, as assessed by in vivo 2-photon microscopy. This results in reduced vascular dysfunction as shown by the shift from a pro- to an anti-inflammatory vascular phenotype associated with MBL deficiency. We also show that platelets directly bind MBL and that platelets from MBL−/− mice have reduced inflammatory phenotype as indicated by reduced IL-1α (interleukin-1α) content, as early as 6 hours after ischemia. Cultured human brain endothelial cells subjected to oxygen-glucose deprivation and exposed to platelets from MBL−/− mice present less cell death and lower CXCL1 (chemokine [C-X-C motif] ligand 1) release (downstream to IL-1α) than those exposed to wild-type platelets. In turn, MBL deposition on ischemic vessels significantly decreases after ischemia in mice treated with IL-1 receptor antagonist compared with controls, indicating a reciprocal interplay between MBL and IL-1α facilitating endothelial damage. Conclusions— We propose MBL as a hub of pathogenic vascular events. It acts as an early trigger of platelet IL-1α release, which in turn favors MBL deposition on ischemic vessels promoting an endothelial pro-inflammatory phenotype.
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Affiliation(s)
- Franca Orsini
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy (F.O., S.F., D.D.B., R.Z., M.-G.D.S.)
| | - Stefano Fumagalli
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy (F.O., S.F., D.D.B., R.Z., M.-G.D.S.)
| | - Eszter Császár
- Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary (E.C., K.T., N.L., A.D.)
| | - Krisztina Tóth
- Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary (E.C., K.T., N.L., A.D.)
| | - Daiana De Blasio
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy (F.O., S.F., D.D.B., R.Z., M.-G.D.S.)
| | - Rosalia Zangari
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy (F.O., S.F., D.D.B., R.Z., M.-G.D.S.)
| | - Nikolett Lénárt
- Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary (E.C., K.T., N.L., A.D.)
| | - Ádám Dénes
- Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary (E.C., K.T., N.L., A.D.)
| | - Maria-Grazia De Simoni
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy (F.O., S.F., D.D.B., R.Z., M.-G.D.S.)
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Michalski M, Świerzko AS, Sawicki S, Kałużyński A, Łukasiewicz J, Maciejewska A, Wydra D, Cedzyński M. Interactions of ficolin-3 with ovarian cancer cells. Immunobiology 2019; 224:316-324. [PMID: 30846332 DOI: 10.1016/j.imbio.2019.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 01/25/2019] [Accepted: 01/25/2019] [Indexed: 11/18/2022]
Abstract
BACKGROUND Ficolin-3 is a pattern-recognition molecule with the ability to activate the lectin pathway of complement. It is found in lung, liver and blood, but its physiological role is unclear. We have investigated interaction of recombinant ficolin-3 with malignant cells and tissues. MATERIAL AND METHODS Cells of various lines of human origin as well as ovarian tissue sections have been studied with the use of flow cytometry and immunohistochemistry. RESULTS Recombinant (but not serum-derived) ficolin-3 was found to bind strongly to the ovarian cancer cell lines, SKOV-3, OVCAR-3 and ES-2, at concentrations of 2.5 μg/ml and above. Moreover, His-tagged recombinant ficolin-3 (10 μg/ml) preferentially stained ovarian tissue sections from patients with malignant tumours compared with those from patients without. Binding to cell lines was inhibited by EDTA and specific carbohydrate ligands, indicating involvement of the fibrinogen-like domain. Binding was enhanced under mildly acidic conditions and at physiological pH after pre-incubation of cells with mildly acidic buffer. CONCLUSION Basing on data concerning recombinant protein, it may be suggested that ficolin-3 is involved in immune response in ovarian cancer. However, unidentified serum factor(s) seem(s) to protect cancer cells from recognition by natural or rficolin-3.
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Affiliation(s)
- Mateusz Michalski
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | - Anna S Świerzko
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
| | - Sambor Sawicki
- Department of Gynaecology, Oncologic Gynaecology and Gynaecologic Endocrinology, Medical University of Gdansk, Gdansk, Poland
| | - Andrzej Kałużyński
- Department of Clinical Pathomorphology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Jolanta Łukasiewicz
- Department of Immunochemistry, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Anna Maciejewska
- Department of Immunochemistry, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Dariusz Wydra
- Department of Gynaecology, Oncologic Gynaecology and Gynaecologic Endocrinology, Medical University of Gdansk, Gdansk, Poland
| | - Maciej Cedzyński
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
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Li J, Li H, Yu Y, Liu Y, Liu Y, Ma Q, Zhang L, Lu X, Wang XY, Chen Z, Zuo D, Zhou J. Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE 2 pathway. Oncoimmunology 2018; 8:e1527650. [PMID: 30713782 DOI: 10.1080/2162402x.2018.1527650] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/18/2018] [Accepted: 09/20/2018] [Indexed: 12/29/2022] Open
Abstract
Mannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain largely unknown. Here, using a murine hepatocellular carcinoma (HCC) model, we showed that MBL was a component of liver microenvironment and MBL-deficient (MBL-/-) mice exhibited an enhanced tumor growth compared with wild-type (WT) mice. This phenomenon was associated with elevation of myeloid derived suppressed cells (MDSCs) in tumor tissue of MBL-/- mice. MBL deficiency also resulted in an increase of activated hepatic stellate cells (HSCs), which showed enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Pharmacological inhibition of COX-2 in vivo partially abrogated the MBL deficiency-promoted tumor growth and MDSC accumulation. Mechanistic studies revealed that MBL could interact directly with HSCs and inhibit HCC-induced HSCs activation via downregulating the extracellular signal-regulated kinase (ERK)/COX-2/PGE2 signaling pathway. Furthermore, MBL-mediated suppression of HCC is validated by administration of MBL-expressing, liver-specific adeno-associated virus (AAV), which significantly inhibited HCC progression in MBL-/- mice. Taken together, these data reveal that MBL may impact on tumor development by shaping the tumor microenvironment via its interaction with the local stromal cells, and also suggests its potential therapeutic use for the treatment of HCC.
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Affiliation(s)
- Junru Li
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Huifang Li
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu Yu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yunzhi Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiang Ma
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Liyun Zhang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiao Lu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, USA
| | - Zhengliang Chen
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, Guangdong, China
| | - Daming Zuo
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, Guangdong, China.,Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangdong, China.,Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangdong, China
| | - Jia Zhou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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11
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Shen Y, Shao Y, Cui Y, Zhao X, Zhang W, Li C. Novel C-type lectin from razor clam Sinonovacula constricta agglutinates bacteria and erythrocytes in a Ca 2+-dependent manner. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2018; 86:9-16. [PMID: 29723812 DOI: 10.1016/j.dci.2018.04.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/19/2018] [Accepted: 04/21/2018] [Indexed: 06/08/2023]
Abstract
Among its other physiological roles, C-type lectins functioned as pattern recognition receptors (PRR) in innate immunity received much attention. In the present study, a novel C-type lectin was identified and characterized from the invertebrate razor clam Sinonovacula constrict and designated as ScCTL. The complete cDNA sequence of ScCTL was 828 bp in length and coded a secreted polypeptide of 158 amino acids with a typical CRD domain. Multiple sequence alignments combined with phylogenetic analysis both collectively confirmed that ScCTL was a novel member belong to lectin family. Spatial expression distribution analysis revealed that ScCTL was extensively expressed in all of the examined tissues, and the highest expression was detected in the hepatopancreas. After 1 × 107 CFU/mL Vibrio parahaemolyticus challenge by immersion infection, the ScCTL transcript in hepatopancreas and gill were markedly upregulated and arrived the maximum levels at 24 or 12 h after challenge, respectively. Recombinant ScCTL could agglutinate not only all tested bacteria but sheep and mouse erythrocyte in the presence of Ca2+. All of our studies suggested that ScCTL performed important roles in protecting cells from pathogenic infection in S. constrict.
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Affiliation(s)
- Yaoyao Shen
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Yina Shao
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China.
| | - Yi Cui
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Xuelin Zhao
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Weiwei Zhang
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Chenghua Li
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China.
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12
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Crystal structure of DlyL, a mannose-specific lectin from Dioclea lasiophylla Mart. Ex Benth seeds that display cytotoxic effects against C6 glioma cells. Int J Biol Macromol 2018; 114:64-76. [DOI: 10.1016/j.ijbiomac.2018.03.080] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/28/2018] [Accepted: 03/16/2018] [Indexed: 12/27/2022]
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13
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Brazil JC, Sumagin R, Stowell SR, Lee G, Louis NA, Cummings RD, Parkos CA. Expression of Lewis-a glycans on polymorphonuclear leukocytes augments function by increasing transmigration. J Leukoc Biol 2017; 102:753-762. [PMID: 28600306 DOI: 10.1189/jlb.1ma0117-013r] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 03/31/2017] [Accepted: 04/09/2017] [Indexed: 12/17/2022] Open
Abstract
PMN-expressed fucosylated glycans from the Lewis glycan family, including Lewis-x (Lex) and sialyl Lewis-x (sLex), have previously been implicated in the regulation of important PMN functions, including selectin-mediated trafficking across vascular endothelium. Although glycans, such as Lex and sLex, which are based on the type 2 sequence (Galβ1-4GlcNAc-R), are abundant on PMNs, the presence of type 1 Galβ1-3GlcNAc-R glycans required for PMN expression of the closely related stereoisomer of Lex, termed Lewis-A (Lea), has not, to our knowledge, been reported. Here, we show that Lea is abundantly expressed by human PMNs and functionally regulates PMN migration. Using mAbs whose precise epitopes were determined using glycan array technology, Lea function was probed using Lea-selective mAbs and lectins, revealing increased PMN transmigration across model intestinal epithelia, which was independent of epithelial-expressed Lea Analyses of glycan synthetic machinery in PMNs revealed expression of β1-3 galactosyltransferase and α1-4 fucosyltransferase, which are required for Lea synthesis. Specificity of functional effects observed after ligation of Lea was confirmed by failure of anti-Lea mAbs to enhance migration using PMNs from individuals deficient in α1-4 fucosylation. These results demonstrate that Lea is expressed on human PMNs, and its specific engagement enhances PMN migration responses. We propose that PMN Lea represents a new target for modulating inflammation and regulating intestinal, innate immunity.
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Affiliation(s)
- Jennifer C Brazil
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA; .,Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Ronen Sumagin
- Department of Pathology, Emory University, Atlanta, Georgia, USA.,Department of Pathology, Northwestern University; Chicago, Illinois, USA
| | - Sean R Stowell
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Goo Lee
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Nancy A Louis
- Department of Neonatal-Perinatal Medicine, Emory University, Atlanta, Georgia, USA; and
| | - Richard D Cummings
- Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Charles A Parkos
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Pathology, Emory University, Atlanta, Georgia, USA
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14
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Radnay ZB, Udvardy M, Papp M, Hársfalvi J, Rejto L, Pál I, Illés Á, Kiss A. Evaluation of Mannose-Binding Lectin is a Useful Approach to Predict the Risk of Infectious Complications Following Autologous Hematopoietic Stem Cell Transplantation. Transplant Proc 2017; 48:3397-3405. [PMID: 27931588 DOI: 10.1016/j.transproceed.2016.08.041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 07/27/2016] [Accepted: 08/22/2016] [Indexed: 01/03/2023]
Abstract
Hematopoietic stem cell transplantation (HSCT) associated immunocompromised state carries high risk of infectious complications. Mannose-binding lectin (MBL) is an acute phase protein involved in innate immune response. Serum MBL level is genetically determined and quite stable. According to literature, significant association was shown between low MBL concentrations and serious infections. The association between serum MBL level and frequency and severity of infections was studied in 186 patients following autologous HSCT. Double-monoclonal antibody sandwich enzyme-linked immunosorbent assay was used to determine MBL antigen level in sera. MBL levels were measured around 100 days following transplantation, in a period without active infection. Twenty-one patients (11%) were MBL deficient. The median time of first infection and number of infections during the first year post-transplantation were not significantly different between patients with MBL deficiency and those without MBL deficiency. The occurrence and number of infections after HSCT correlated with the MBL/C-reactive protein ratio. The number of severe infections was not higher among those with MBL deficiency. The occurrence of infections after the pre-engraftment period during the first year post-transplantation was significantly different in patient groups separated by MBL cut-off level. The MBL/C-reactive protein ratio might be a useful marker of infectious complications. MBL measurement may be helpful in antibiotic treatment. In case of MBL deficiency, earlier and more intensive treatment may be indicated.
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Affiliation(s)
- Z B Radnay
- Department of Hematology, Institute for Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
| | - M Udvardy
- Department of Hematology, Institute for Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - M Papp
- Department of Gastroenterology, Institute for Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - J Hársfalvi
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary; Clinical Research Center, Faculty of Medicine, University of Debrecen, Hungary
| | - L Rejto
- Department of Hematology, Institute for Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - I Pál
- Department of Hematology, Institute for Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Á Illés
- Department of Hematology, Institute for Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - A Kiss
- Department of Hematology, Institute for Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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15
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Jayanthi S, Ishwarya R, Anjugam M, Iswarya A, Karthikeyan S, Vaseeharan B. Purification, characterization and functional analysis of the immune molecule lectin from the haemolymph of blue swimmer crab Portunus pelagicus and their antibiofilm properties. FISH & SHELLFISH IMMUNOLOGY 2017; 62:227-237. [PMID: 28110033 DOI: 10.1016/j.fsi.2017.01.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 01/09/2017] [Accepted: 01/13/2017] [Indexed: 06/06/2023]
Abstract
The present study reveals purification and characterization of immune molecule lectin from the haemolymph of blue swimmer crab Portunus pelagicus (Pp-Lec). The Pp-Lec was purified by affinity chromatography with mannose coupled sepharose CL-4B column and it exhibits single band with a molecular weight of 155 kDa in SDS-PAGE. The surface morphology of purified Pp-Lec displays the homogeneous nature of protein. A distinct peak with a retention time of 3.3 min was appeared in high performance liquid chromatography (HPLC) and X-ray diffraction (XRD) analysis expresses a single peak at 31.5° which shows the purity and crystalline nature of the protein respectively. Functional analysis of purified Pp-Lec exhibits encapsulation activity against sepharose beads and yeast agglutination activity against Saccharomyces cerevisiae. Moreover, the purified Pp-Lec has the ability to agglutinates with the human erythrocytes among tested and which was observed by light microscopy. In addition, purified Pp-Lec showed the broad spectrum of antibacterial activity against Gram-positive Bacillus pumulis, Bacillus thuringiensis, Enterococcus faecalis and Gram negative Citrobacter amalonaticus, Vibrio parahaemolyticus, Pseudomonas aeruginosa, Proteus vulgaris, Citrobacter murliniae, Citrobacter freundii, Morganella morganii. Antibiofilm potential of purified Pp-Lec against selective Gram-negative bacteria showed the disruption of biofilm architecture at the concentration of 50 μg ml-1.
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Affiliation(s)
- Sangily Jayanthi
- Crustacean Molecular Biology and Genomics Division, Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Science Block 4th Floor, Burma Colony, Karaikudi 630004, Tamil Nadu, India
| | - Ramachandran Ishwarya
- Crustacean Molecular Biology and Genomics Division, Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Science Block 4th Floor, Burma Colony, Karaikudi 630004, Tamil Nadu, India
| | - Mahalingam Anjugam
- Crustacean Molecular Biology and Genomics Division, Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Science Block 4th Floor, Burma Colony, Karaikudi 630004, Tamil Nadu, India
| | - Arokiadhas Iswarya
- Crustacean Molecular Biology and Genomics Division, Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Science Block 4th Floor, Burma Colony, Karaikudi 630004, Tamil Nadu, India
| | | | - Baskaralingam Vaseeharan
- Crustacean Molecular Biology and Genomics Division, Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Science Block 4th Floor, Burma Colony, Karaikudi 630004, Tamil Nadu, India.
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16
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Association of MBL2 exon1 polymorphisms with high-risk human papillomavirus infection and cervical cancers: a meta-analysis. Arch Gynecol Obstet 2016; 294:1109-1116. [PMID: 27619685 DOI: 10.1007/s00404-016-4201-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 09/06/2016] [Indexed: 10/21/2022]
Abstract
PURPOSE High-risk human papillomavirus (HR-HPV) infection is the main known cause of cervical cancer. Mannose-binding lectin (MBL) is a recognition molecule that mediates phagocytosis and activates complement. METHODS We performed a meta-analysis to investigate the association of MBL-2 functional polymorphisms with HPV infection and cervical cancer (CC). RESULTS The meta-analyses indicated an association between the MBL2 exon 1 polymorphisms and susceptibility to HPV infection in the recessive model (OO vs. AA + AO, p = 0.042, 95 % CI 1.02-3.15), and O/O vs. A/A mode (P = 0.023, 95 % CI 1.10-3.40) in Caucasian. Meanwhile, there was a significant association between MBL2 exon 1 polymorphisms and cervical cancer risk in AO vs. AA model (p = 0.035, 95 % CI 1.03-2.26), and Allelic model (O vs. A, p = 0.022, 95 % CI 1.05-1.96) as compared to HR-HPV-infected patients with CC vs. healthy controls in Caucasian. In addition, no an association was observed between MBL2 -550 H/L and -221 X/Y polymorphisms and HPV infection among Caucasians, but we found an association between the MBL2 -550 H/L polymorphism and susceptibility to HR-HPV infection in recessive model (HH vs. LL + LH, p = 0.003, 95 % CI 1.18-2.23), HH vs. LL model (p = 0.021, 95 % CI 1.07-2.19), and allelic model(H vs. L, p = 0.042, 95 % CI 1.01-1.40) in Asians. CONCLUSIONS Collectively, we suggest that the MBL2 gene exon1 polymorphisms are associated with increased risk of high-risk HPV infection and cervical cancer development among Caucasians. Additionally, no significant association was found between the MBL2 -550 H/L or -221 X/Y polymorphisms and HPV infection in Caucasians, but there may be potential links in Asians.
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17
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Association between mannose-binding lectin variants, haplotypes and risk of hepatocellular carcinoma: A case-control study. Sci Rep 2016; 6:32147. [PMID: 27557564 PMCID: PMC4997250 DOI: 10.1038/srep32147] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 08/03/2016] [Indexed: 12/13/2022] Open
Abstract
The innate immunity gene mannose-binding lectin2 (MBL2) has played an important role in hepatitis B virus (HBV) infection, and the relationship between MBL2 variants and hepatocellular carcinoma (HCC) risk has not yet been identified. In total, 315 HCC cases and 315 healthy controls were enrolled and blood samples were acquired. High resolution melt analysis (HRM) was employed to genotype 6 polymorphisms in MBL2 gene. Increased HCC risk in carriers of LL genotype of -550 polymorphism with an adjusted OR (AOR) of 1.61 (95%CI = 1.00-2.57) was observed but no significant association detected in HL genotype. Both YX and XX genotype demonstrated a significantly elevated HCC risk in the analysis of -221 polymorphism. The B variants in codon 54 was also significantly associated with elevated HCC risk. HYB was identified as the protective factor of HCC while LXB was significantly associated with increase HCC risk. ELISA technique revealed that the MBL2 protein was significantly reduced in HCC cases. Moreover, both IL-1β and IL-6 were inversely associated with plasma MBL2 level.The mutations in MBL2 could lead to compromised innate immunity, and possibly lead to elevated HCC risk, and a novel haplotype HXB has been identified with a rate of 12.5%.
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18
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Świerzko AS, Bartłomiejczyk MA, Brzostek A, Łukasiewicz J, Michalski M, Dziadek J, Cedzyński M. Mycobacterial antigen 85 complex (Ag85) as a target for ficolins and mannose-binding lectin. Int J Med Microbiol 2016; 306:212-21. [PMID: 27141819 DOI: 10.1016/j.ijmm.2016.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 03/07/2016] [Accepted: 04/25/2016] [Indexed: 10/21/2022] Open
Abstract
The pattern recognition molecules (PRMs) able to activate complement via the lectin pathway are suspected to be involved in the interaction between pathogenic Mycobacteria and the host immune response. Recently, we have found strong interactions between 25 and 35kDa mycobacterial cell fractions and mannose-binding lectin (MBL) and ficolins. Here we demonstrate that two biologically important mycobacterial structures, mannosylated lipoarabinomannan (ManLAM) and the antigen 85 (Ag85) complex, induce activation of the lectin pathway of complement. The strong interaction of recombinant MBL with purified ManLAM was confirmed, but no binding of recombinant ficolins (ficolin-1, -2, -3) with this structure was observed. Interestingly, all PRMs tested reacted with the mycobacterial antigen 85 (Ag85) complex. Based on the use of specific inhibitors (mannan for MBL, acetylated bovine serum albumin for ficolin-1 and -2, Hafnia alvei PCM 1200 lipopolysaccharide for ficolin-3), we concluded that carbohydrate-recognition (MBL) and fibrinogen-like domains (ficolins) were involved in these interactions. Our results indicate that the mycobacterial antigen 85 complex is a target for ficolins and MBL. Furthermore, those PRMs also bound to fibronectin and therefore might influence the Ag85 complex-dependent interaction of Mycobacterium with the extracellular matrix.
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Affiliation(s)
- Anna S Świerzko
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Marcin A Bartłomiejczyk
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Anna Brzostek
- Laboratory of Mycobacterium Genetics and Physiology, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Jolanta Łukasiewicz
- Department of Immunochemistry, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wroclaw, Poland
| | - Mateusz Michalski
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Jarosław Dziadek
- Laboratory of Mycobacterium Genetics and Physiology, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Maciej Cedzyński
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
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19
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Efficient Synthesis of the Lewis A Tandem Repeat. Molecules 2016; 21:molecules21050614. [PMID: 27187324 PMCID: PMC6272916 DOI: 10.3390/molecules21050614] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 05/04/2016] [Accepted: 05/06/2016] [Indexed: 12/25/2022] Open
Abstract
The convergent synthesis of the Lewis A (Le(a)) tandem repeat is described. The Le(a) tandem repeat is a carbohydrate ligand for a mannose binding protein that shows potent inhibitory activity against carcinoma growth. The Le(a) unit, {β-d-Gal-(1→3)-[α-l-Fuc-(1→4)]-β-d-GlcNAc}, was synthesized by stereoselective nitrile-assisted β-galactosylation with the phenyl 3-O-allyl-2,4,6-tri-O-benzyl-1-thio-β-galactoside, and ether-assisted α-fucosylation with fucosyl (N-phenyl)trifluoroacetimidate. This common Le(a) unit was easily converted to an acceptor and donor in high yields, and the stereoselective assembly of the hexasaccharide and dodecasaccharide as the Le(a) tandem repeat framework was achieved by 2-trichloroacetamido-assisted β-glycosylation and the (N-phenyl)trifluoroacetimidate method.
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20
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Biological role of mannose binding lectin: From newborns to centenarians. Clin Chim Acta 2015; 451:78-81. [DOI: 10.1016/j.cca.2015.03.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 03/04/2015] [Accepted: 03/08/2015] [Indexed: 11/19/2022]
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21
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Li T, Dong ZR, Guo ZY, Wang CH, Zhi XT, Zhou JW, Li DK, Chen ZT, Chen ZQ, Hu SY. Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBβ/NF-κB pathway. Liver Int 2015; 35:1416-29. [PMID: 25066210 DOI: 10.1111/liv.12644] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 07/23/2014] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Elevation of high-mannose glycans is a common feature of malignant cells and has been suggested to be the basis for alternative cancer therapy for several years. Here we want to investigate the antitumour effect of pseudomonas aeruginosa-mannosesensitive haemagglutinin (PA-MSHA), a genetically engineered heat-inactivated PA strain with mannose-sensitive binding activity, on hepatocellular carcinoma (HCC). METHODS Tumourigenicity and metastatic potentials of HCC were studied after PA-MSHA treatment by utilizing the in vitro/in vivo model of HCC. Expression of apoptosis-associated proteins and epithelial-mesenchymal transition (EMT) related genes were evaluated, and possible signalling pathways involved were investigated. RESULTS PA-MSHA induced significant cell proliferation inhibition and cell cycle arrest of HCC through decreasing the levels of cyclins D1, cyclins E, CDK2, CDK4, proliferating cell nuclear antigen (PCNA), and increasing the level of p21 and p27. Moreover, PA-MSHA suppressed the invasion, migration and adhesion of HCC through inhibiting epithelial-mesenchymal transition (EMT). PA-MSHA also inhibited EGFR/Akt/IκBβ/NF-κB pathway and overexpression of NF-κB significantly abrogated PA-MSHA induced EMT inhibition. In addition, competitive inhibition of the mannose binding activity of PA-MSHA by D-mannose significantly blocked its effect on cell cycle arrest and EMT. PA-MSHA also abrogated lung metastasis of HCC and significantly inhibited tumour growth in the in vivo study. CONCLUSIONS Our study demonstrated the essential role of EGFR/Akt/IκBβ/NF-κB pathway in the inhibitory effect of PA-MSHA on invasion and metastasis of HCC through suppressing EMT, and revealed an attractive prospect of PA-MSHA as a novel candidate agent in the treatment of HCC.
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Affiliation(s)
- Tao Li
- Department of general surgery, Qilu Hospital, Shandong University, Jinan, 250012, China
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22
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Zupin L, Polesello V, Casalicchio G, Freato N, Maestri I, Comar M, Crovella S, Segat L. MBL2 polymorphisms in women with atypical squamous cells of undetermined significance. J Med Virol 2015; 87:851-9. [PMID: 25693844 DOI: 10.1002/jmv.24080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2014] [Indexed: 01/02/2023]
Abstract
Infection with high risk Human papillomavirus (HPV) is the main known cause of cervical cancer. HPV induces different grades of lesions: among them, Atypical squamous cells of undetermined significance are abnormal lesions that could evolve in pre-cancer lesions or spontaneously regress. The mannose binding lectin (MBL) is an innate immunity serum protein also found in cervico-vaginal mucosa, whose expression is known to be affected by polymorphisms in exon 1 and promoter of the MBL2 gene. In the present study the possible association between MBL2 functional polymorphisms and susceptibility to develop atypical squamous cells of undetermined significance was investigated in a group of women from North-East of Italy, stratified for HPV infection status. The MBL2 D and O alleles and the deficient producer combined genotypes, responsible for low MBL production, were more represented among atypical squamous cells of undetermined significance positive women than healthy controls and the results were confirmed when only HPV negative samples were considered. These results suggest a possible involvement of MBL2 functional polymorphisms in atypical squamous cells of undetermined significance susceptibility.
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Affiliation(s)
- Luisa Zupin
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
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23
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Mannan-binding lectin polymorphisms and serum levels in patients with endometriosis. Eur J Obstet Gynecol Reprod Biol 2014; 181:256-8. [DOI: 10.1016/j.ejogrb.2014.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Revised: 07/30/2014] [Accepted: 08/07/2014] [Indexed: 11/23/2022]
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Swierzko AS, Szala A, Sawicki S, Szemraj J, Sniadecki M, Sokolowska A, Kaluzynski A, Wydra D, Cedzynski M. Mannose-Binding Lectin (MBL) and MBL-associated serine protease-2 (MASP-2) in women with malignant and benign ovarian tumours. Cancer Immunol Immunother 2014; 63:1129-40. [PMID: 25038892 PMCID: PMC4209098 DOI: 10.1007/s00262-014-1579-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 07/02/2014] [Indexed: 11/28/2022]
Abstract
Mannose-Binding Lectin (MBL) is a serum pattern recognition molecule, able to activate complement in association with MASP proteases. Serum levels of MBL and MASP-2, activities of MBL-MASP complexes, single nucleotide polymorphisms of the MBL2 and MASP2 genes and/or their specific mRNA expression in ovarian sections were investigated in 128 patients suffering from primary ovarian cancer (OC) and compared with 197 controls (C), encompassing both patients with benign ovarian tumours (n = 123) and others with no ovarian pathology (n = 74). MBL deficiency-associated genotypes were more common among OC patients than among controls. The O/O group of genotypes was associated with ovarian cancer (OR 3.5, p = 0.02). In A/A homozygotes, MBL concentrations and activities were elevated in the OC group and correlated with C-reactive protein. Moreover, high MBL serum levels were associated with more advanced disease stage. No differences in distribution of the MASP2 +359 A>G (D120G) SNP or MASP-2 serum levels were found between cancer patients and their controls. However, the highest frequency of the A/G (MASP2) and LXA/O or O/O (MBL2) genotypes was found among OC patients with tumours of G1-2 grade (well/moderately differentiated). Furthermore, MBL deficiency-associated genotypes predicted prolonged survival. None of the parameters investigated correlated with CA125 antigen or patients' age. The local expression of MBL2 and MASP2 genes was higher in women with ovarian cancer compared with controls. It is concluded that the expression of MBL and MASP-2 is altered in ovarian cancer, possibly indicating involvement of the lectin pathway of complement activation in the disease.
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Affiliation(s)
- Anna St Swierzko
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland
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Teodorof C, Divakar S, Soontornniyomkij B, Achim CL, Kaul M, Singh KK. Intracellular mannose binding lectin mediates subcellular trafficking of HIV-1 gp120 in neurons. Neurobiol Dis 2014; 69:54-64. [PMID: 24825317 DOI: 10.1016/j.nbd.2014.05.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 04/26/2014] [Accepted: 05/02/2014] [Indexed: 01/19/2023] Open
Abstract
Human immunodeficiency virus-1 (HIV-1) enters the brain early during infection and leads to severe neuronal damage and central nervous system impairment. HIV-1 envelope glycoprotein 120 (gp120), a neurotoxin, undergoes intracellular trafficking and transport across neurons; however mechanisms of gp120 trafficking in neurons are unclear. Our results show that mannose binding lectin (MBL) that binds to the N-linked mannose residues on gp120, participates in intravesicular packaging of gp120 in neuronal subcellular organelles and also in subcellular trafficking of these vesicles in neuronal cells. Perinuclear MBL:gp120 vesicular complexes were observed and MBL facilitated the subcellular trafficking of gp120 via the endoplasmic reticulum (ER) and Golgi vesicles. The functional carbohydrate recognition domain of MBL was required for perinuclear organization, distribution and subcellular trafficking of MBL:gp120 vesicular complexes. Nocodazole, an agent that depolymerizes the microtubule network, abolished the trafficking of MBL:gp120 vesicles, suggesting that these vesicular complexes were transported along the microtubule network. Live cell imaging confirmed the association of the MBL:gp120 complexes with dynamic subcellular vesicles that underwent trafficking in neuronal soma and along the neurites. Thus, our findings suggest that intracellular MBL mediates subcellular trafficking and transport of viral glycoproteins in a microtubule-dependent mechanism in the neurons.
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Affiliation(s)
- C Teodorof
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - S Divakar
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - B Soontornniyomkij
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - C L Achim
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - M Kaul
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Sanford-Burnham Medical Research Institute, 10901 N Torrey Pines Rd, La Jolla, CA, USA
| | - K K Singh
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
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Nonaka M, Imaeda H, Matsumoto S, Yong Ma B, Kawasaki N, Mekata E, Andoh A, Saito Y, Tani T, Fujiyama Y, Kawasaki T. Mannan-binding protein, a C-type serum lectin, recognizes primary colorectal carcinomas through tumor-associated Lewis glycans. THE JOURNAL OF IMMUNOLOGY 2014; 192:1294-301. [PMID: 24391218 DOI: 10.4049/jimmunol.1203023] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mannan (mannose)-binding protein (MBP) is a C-type serum lectin that plays a key role in innate immunity. MBP forms large multimers (200-600 kDa) and exhibits broad specificity for mannose, N-acetylglucosamine, and fucose. MBP exhibits high affinity for unique oligosaccharides that have been isolated from human colorectal carcinoma (SW1116) cells and characterized as highly fucosylated high m.w. type 1 Lewis glycans. In this study, we first demonstrated that MBP recognizes human primary colorectal carcinoma tissues through tumor-associated MBP ligands. We performed fluorescence-based histochemistry of MBP in human colorectal carcinoma tissues and showed that MBP clearly stained cancer mucosae in a Ca(2+)-dependent manner. Coincubation with plant (Aleuria aurantia) lectin, but not Con A, blocked MBP staining, indicating that fucose, rather than mannose, is involved in this interaction. The expression of MBP ligands was detected in 127 of 330 patients (38.5%), whereas, most significantly, there was no expression in 69 nonmalignant tissues. The MBP-staining pattern in cancer mucosae significantly overlapped with that of Lewis b [Fucα1-2Galβ1-3(Fucα1-4)GlcNAc] staining, but the Lewis b staining in normal tissues was not associated with MBP staining. In addition, the MBP staining correlated inversely with the expression of CA19-9 Ag, and MBP stained 11 of 25 (44%) CA19-9 (sialyl Lewis a [NeuAc(α2-3)Galβ1-3(Fucα1-4)GlcNAc])(-) colorectal carcinoma tissues. We found a favorable prognosis in patients with MBP ligand(+) tumors. These results suggest that selective recognition of cancer cells by endogenous MBP seems to be associated with an antitumor effect and that tissue staining with MBP in combination with CA19-9 may serve as a novel indicator of colorectal carcinoma tissues.
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Affiliation(s)
- Motohiro Nonaka
- Research Center for Glycobiotechnology, Ritsumeikan University, Shiga 525-8577, Japan
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Charbonneau B, Goode EL, Kalli KR, Knutson KL, Derycke MS. The immune system in the pathogenesis of ovarian cancer. Crit Rev Immunol 2013; 33:137-64. [PMID: 23582060 DOI: 10.1615/critrevimmunol.2013006813] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Clinical outcomes in ovarian cancer are heterogeneous even when considering common features such as stage, response to therapy, and grade. This disparity in outcomes warrants further exploration into tumor and host characteristics. One compelling host characteristic is the immune response to ovarian cancer. While several studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease, recent genetic and protein analyses also suggest a role in disease incidence. Recent studies also show that anti-tumor immunity is often negated by immune suppressive cells present in the tumor microenvironment. These suppressive immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathologic network. Thus, future research into immunotherapy targeting ovarian cancer will likely become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression or by disrupting critical cytokine networks.
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Affiliation(s)
- Bridget Charbonneau
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
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Wang Y, Chen AD, Lei YM, Shan GQ, Zhang LY, Lu X, Chen ZL. Mannose-binding lectin inhibits monocyte proliferation through transforming growth factor-β1 and p38 signaling pathways. PLoS One 2013; 8:e72505. [PMID: 24039775 PMCID: PMC3765169 DOI: 10.1371/journal.pone.0072505] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Accepted: 07/10/2013] [Indexed: 12/27/2022] Open
Abstract
Mannose-binding lectin (MBL), a plasma C-type lectin, plays an important role in innate immunity. However, the interaction, and the consequences of it, between MBL and the immune system remain ill defined. We have investigated the contributing mechanisms and effects of MBL on the proliferation of human monocytes. At lower concentrations (≤4 μg/ml) MBL was shown to partially enhance monocyte proliferation. By contrast, at higher concentrations (8–20 μg/ml) of MBL, cell proliferation was markedly attenuated. MBL-induced growth inhibition was associated with G0/G1 arrest, down-regulation of cyclin D1/D3, cyclin-dependent kinase (Cdk) 2/Cdk4 and up-regulation of the Cdk inhibitory protein Cip1/p21. Additionally, MBL induced apoptosis, and did so through caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage. Moreover, transforming growth factor (TGF)-β1 levels increased in the supernatants of MBL-stimulated monocyte cultures. We also found that MBL-dependent inhibition of monocyte proliferation could be reversed by the TGF-β receptor antagonist SB-431542, or by anti-TGF-β1 antibody, or by the mitogen-activated protein kinase (MAPK) inhibitors specific for p38 (SB203580), but not ERK (U0126) or JNK (SP600125). Thus, at high concentrations, MBL can affect the immune system by inhibiting monocyte proliferation, which suggests that MBL may exhibit anti-inflammatory effects.
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Affiliation(s)
- Yan Wang
- Department of Immunology, Southern Medical University, Guangzhou, Guangdong, China
- Department of Microbiology and Immunology, School of Basic Medicine, Guangdong Medical College, Dongguan, Guangdong, China
| | - A-De Chen
- Department of Immunology, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan-Mei Lei
- Department of Immunology, Southern Medical University, Guangzhou, Guangdong, China
| | - Gui-Qiu Shan
- Department of Immunology, Southern Medical University, Guangzhou, Guangdong, China
| | - Li-Yun Zhang
- Department of Immunology, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiao Lu
- Department of Immunology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zheng-Liang Chen
- Department of Immunology, Southern Medical University, Guangzhou, Guangdong, China
- * E-mail:
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Lu Y, Sun G, Liu G, Shi Y, Han Y, Yu F, Xiang X, Li W, Xiao H, Liu X, Li S. Clinical significance of mannose-binding lectin expression in thyroid carcinoma tissues. Pathol Oncol Res 2012; 19:259-66. [PMID: 23250731 DOI: 10.1007/s12253-012-9577-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Accepted: 09/24/2012] [Indexed: 11/26/2022]
Abstract
Mannose-binding lectin (MBL) plays an important role in the host defence against pathogens and carcinogenesis. This study aimed to analyze differential expression of MBL protein in thyroid cancer tissues and then to investigate the effects of rhMBL in thyroid cancer cells. Tissue specimens from 45 thyroid carcinoma patients and 45 adenoma patients were recruited for immunohistochemical analysis of MBL expression. Cell viability, apoptosis, RT-PCR and Western blot assays were used to detect changes in tumor cell viability, apoptosis, and gene expression, respectively, after treatment of thyroid cancer cells with rhMBL. MBL was differentially expressed in papillary thyroid carcinoma, adenoma, and the distant normal tissues (0.322 ± 0.008, 0.227 ± 0.003, and 0.113 ± 0.003, respectively, P < 0.05). MBL expression was associated with the advanced disease stage, histological grade, or lymph node metastasis in cancer patients (P < 0.05). Moreover, rhMBL treatment of thyroid cancer cells reduced tumor cell viability but induced apoptosis in a dose- and time-dependent manner. rhMBL treatment also downregulated Bcl2 protein expression in thyroid cancer cells (P < 0.05). In addition, expression p53 protein was increased in thyroid cancer cells after rhMBL treatment (P < 0.05). The data from the current study demonstrate that MBL overexpression is associated with advanced thyroid carcinomas, and rhMBL treatment significantly reduced viability but induced apoptosis of thyroid cancer cell lines. Further studies will clarify whether overexpressed MBL in thyroid cancer tissues is functional.
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Affiliation(s)
- Yifang Lu
- Department of Endocrinology (Section I), Tangshan Workers Hospital, Tangshan, China
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Swierzko AS, Kilpatrick DC, Cedzynski M. Mannan-binding lectin in malignancy. Mol Immunol 2012; 55:16-21. [PMID: 23062612 DOI: 10.1016/j.molimm.2012.09.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 09/12/2012] [Accepted: 09/19/2012] [Indexed: 12/28/2022]
Abstract
Complement may play a dual role in cancer: it may contribute either to the development or to the inhibition of tumour growth. Its components may be candidate biomarkers facilitating the disease detection, its progress or effectiveness of therapy. Additionally, complement deficiencies may increase the risk of infections and contribute to the higher mortality, especially in patients undergoing aggressive chemotherapy. In this paper, possible cancer associations of one of the factors activating complement via the lectin pathway, mannan-binding lectin (MBL), are discussed.
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Affiliation(s)
- Anna S Swierzko
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
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Nevadunsky NS, Korneeva I, Caputo T, Witkin SS. Mannose-binding lectin codon 54 genetic polymorphism and vaginal protein levels in women with gynecologic malignancies. Eur J Obstet Gynecol Reprod Biol 2012; 163:216-8. [PMID: 22633170 PMCID: PMC3823525 DOI: 10.1016/j.ejogrb.2012.04.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 02/17/2012] [Accepted: 04/30/2012] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Mannose-binding lectin (MBL), an innate immune system component that binds to carbohydrates, activates the complement cascade and promotes destruction of microorganisms and abnormal cells. We determined whether a polymorphism in the MBL gene influences vaginal MBL protein concentrations and the occurrence of gynecologic malignancies. STUDY DESIGN DNA from 289 women seen in a gynecologic oncology practice and from 126 healthy women was tested for an MBL codon 54 single nucleotide polymorphism by polymerase chain reaction and endonuclease digestion. Vaginal supernatants from 282 of these women were assayed for MBL protein by ELISA. RESULTS The normal (A,A) genotype was present in 84.1% of 126 healthy women and 85.3% of 95 women with a benign diagnosis as opposed to 70.0% of 70 women with ovarian cancer (p=0.02). The MBL variant allele (allele B) frequency was 8.7% in healthy women, 8.4% in women with a benign diagnosis and 17.1% in women with ovarian cancer (p=0.02). Vaginal MBL protein concentrations were highest in women with the A,A genotype, intermediate in A,B heterozygotes (p<0.0001) and lowest in B,B homozygotes (p=.0097). CONCLUSION The MBL 54 polymorphism and reduction in vaginal MBL concentrations may be a risk factor for development of epithelial ovarian cancer.
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Affiliation(s)
- Nicole S. Nevadunsky
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
| | - Irina Korneeva
- Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
| | - Thomas Caputo
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
| | - Steven S. Witkin
- Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, USA
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Tomaiuolo R, Ruocco A, Salapete C, Carru C, Baggio G, Franceschi C, Zinellu A, Vaupel J, Bellia C, Sasso BL, Ciaccio M, Castaldo G, Deiana L. Activity of mannose-binding lectin in centenarians. Aging Cell 2012; 11:394-400. [PMID: 22239660 PMCID: PMC3935210 DOI: 10.1111/j.1474-9726.2012.00793.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We analyzed MBL2 gene variants in two cohorts of centenarians, octo-nonagenarians and nonagenarians, and in the general population, one from Sardinia Island (Italy), recruited in the frame of the AKea study, and another from Campania (southern Italy), to search for haplotypes related to longevity. We also assessed in vitro the effect of mannose-binding lectin (MBL) on various human cells at different stage of senescence. The frequency of high and null activity haplotypes was significantly lower, and the frequency of intermediate activity haplotype significantly higher in centenarians and in subjects between 80 and 99 years from both the cohorts as compared each to the general population from the same geographic area. Furthermore, serum MBL concentration (also after normalization to serum albumin) was significantly lower in centenarians and in octo- and nonagenarians as compared to the general population, suggesting that intermediate MBL haplotype/activity may be protective. We also demonstrated that in vitro MBL protein bound to senescent IMR90 fibroblasts thereby causing cell lysis, but not to other types of cycle-arrested cells not in senescence. This implicates a novel role of MBL in the clearance of senescent cells.
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Affiliation(s)
- Rossella Tomaiuolo
- CEINGE-Biotecnologie Avanzate scarl, Naples, Italy
- Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy
| | - Anna Ruocco
- CEINGE-Biotecnologie Avanzate scarl, Naples, Italy
- Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy
| | - Chiara Salapete
- CEINGE-Biotecnologie Avanzate scarl, Naples, Italy
- Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy
| | - Ciriaco Carru
- Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy
| | | | - Claudio Franceschi
- Dipartimento di Patologia Sperimentale, Università di Bologna, Bologna, Italy
| | - Angelo Zinellu
- Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy
| | - James Vaupel
- Max Planck Institute for Demographic Research, Rostock, Germany
| | - Chiara Bellia
- Cattedra di Biochimica Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy
| | - Bruna Lo Sasso
- Cattedra di Biochimica Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy
| | - Marcello Ciaccio
- Cattedra di Biochimica Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy
| | - Giuseppe Castaldo
- CEINGE-Biotecnologie Avanzate scarl, Naples, Italy
- Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy
| | - Luca Deiana
- Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy
- Azienda Ospedaliera Universitaria di Sassari, Sassari, Italy
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van der Pol P, Schlagwein N, van Gijlswijk DJ, Berger SP, Roos A, Bajema IM, de Boer HC, de Fijter JW, Stahl GL, Daha MR, van Kooten C. Mannan-binding lectin mediates renal ischemia/reperfusion injury independent of complement activation. Am J Transplant 2012; 12:877-87. [PMID: 22225993 DOI: 10.1111/j.1600-6143.2011.03887.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation-derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL-mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL-mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation.
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Affiliation(s)
- P van der Pol
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
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MBL Deficiency as Risk of Infection and Autoimmunity. ANIMAL LECTINS: FORM, FUNCTION AND CLINICAL APPLICATIONS 2012:933-953. [PMCID: PMC7122001 DOI: 10.1007/978-3-7091-1065-2_42] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
In pathogen recognition by C-type lectins, several levels of complexity can be distinguished; these might modulate the immune response in different ways. Firstly, the pathogen-associated molecular pattern repertoire expressed at the microbial surface determines the interactions with specific receptors (Fig. 42.1). Secondly, each immune cell type possesses a specific set of pathogen-recognition receptors. Thirdly, changes in the cell-surface distribution of C-type lectins regulate carbohydrate binding by modulating receptor affinity for different ligands. Crosstalk between these receptors results in a network of multimolecular complexes, adding a further level of complexity in pathogen recognition (Cambi and Figdor 2005; Thiel et al. 2006) (see 10.1007/978-3-7091-1065-2_23). MBL deficiency is genetically determined and predisposes to recurrent infections and chronic inflammatory diseases. MBL deficiency has been implicated in susceptibility and course of viral, bacterial, fungal, and protozoan infection. More than 10% of the general population may, depending on definition, be classified as MBL deficient, underlining the redundancy of the immune system. MBL-disease association studies have been a fruitful area of research, which implicates a role for MBL in infective, inflammatory and autoimmune disease processes. MBL deficiency predisposes both to infection by extra-cellular pathogens and to autoimmune disease.
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Dursun O, Yilmaz A, Ayaz L, Tamer L. Serum levels and H/L gene polymorphism of mannose-binding lectin in primary open angle glaucoma. Curr Eye Res 2012; 37:212-7. [PMID: 22335808 DOI: 10.3109/02713683.2011.639124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE To analyze the serum levels and H/L gene polymorphisms of mannose-binding lectin-2 (MBL-2) in primary open angle glaucoma (POAG) cases and control subjects to investigate whether MBL-2 has a possible role in the development and pathogenesis of POAG. MATERIALS AND METHODS In 45 POAG cases and age and sex-matched 45 healthy controls, Elisa Kit was used to determine serum levels of MBL-2. The genomic DNA of patient and control groups was extracted from whole blood using High Pure PCR template preparation kit. Genotyping of MBL-2 polymorphisms were detected by using a MBL-2 mutation detection kit in real-time PCR. Chi-square or Fisher's Exact Tests were used to evaluate the distribution of MBL-2 H/L genotypes among patients and control subjects. Associations between the H/L genotype and POAG risk were analyzed by using binary logistic regression. The serum MBL-2 levels of both groups were compared with Independent Sample t-test. RESULTS Mean MBL-2 serum levels in the patient group (21.30 ± 4.97 µg/mL) was significantly higher than the control group (17.48 ± 3.66 µg/mL), (p < 0.001). The distribution of alleles in the patient group was 28.9% for LL, 44.4% for HL, 26.7% for HH and in controls was 33.3% for LL, 37.8% for HL, 28.3% for HH. According to genotype ratios, the two groups were not different from each other. CONCLUSIONS Our findings may suggest an association between high serum MBL-2 levels and POAG, but H/L gene polymorphism of MBL-2 seems not to be associated with POAG.
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Affiliation(s)
- Ozer Dursun
- Mersin State Hospital, Ophthalmology Clinic, Mersin, Turkey
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Tian L, Sun SSM. A cost-effective ELP-intein coupling system for recombinant protein purification from plant production platform. PLoS One 2011; 6:e24183. [PMID: 21918684 PMCID: PMC3168869 DOI: 10.1371/journal.pone.0024183] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 08/02/2011] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Plant bioreactor offers an efficient and economical system for large-scale production of recombinant proteins. However, high cost and difficulty in scaling-up of downstream purification of the target protein, particularly the common involvement of affinity chromatography and protease in the purification process, has hampered its industrial scale application, therefore a cost-effective and easily scale-up purification method is highly desirable for further development of plant bioreactor. METHODOLOGY/PRINCIPAL FINDINGS To tackle this problem, we investigated the ELP-intein coupling system for purification of recombinant proteins expressed in transgenic plants using a plant lectin (PAL) with anti-tumor bioactivity as example target protein and rice seeds as production platform. Results showed that ELP-intein-PAL (EiP) fusion protein formed novel irregular ER-derived protein bodies in endosperm cells by retention of endogenous prolamins. The fusion protein was partially self-cleaved in vivo, but only self-cleaved PAL protein was detected in total seed protein sample and deposited in protein storage vacuoles (PSV). The in vivo uncleaved EiP protein was accumulated up to 2-4.2% of the total seed protein. The target PAL protein could be purified by the ELP-intein system efficiently without using complicated instruments and expensive chemicals, and the yield of pure PAL protein by the current method was up to 1.1 mg/g total seed protein. CONCLUSION/SIGNIFICANCE This study successfully demonstrated the purification of an example recombinant protein from rice seeds by the ELP-intein system. The whole purification procedure can be easily scaled up for industrial production, providing the first evidence on applying the ELP-intein coupling system to achieve cost-effective purification of recombinant proteins expressed in plant bioreactors and its possible application in industry.
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Affiliation(s)
- Li Tian
- School of Life Sciences, Tsinghua University, Beijing, China
- Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - Samuel S. M. Sun
- Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
- * E-mail:
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Ghazarian H, Idoni B, Oppenheimer SB. A glycobiology review: carbohydrates, lectins and implications in cancer therapeutics. Acta Histochem 2011; 113:236-47. [PMID: 20199800 PMCID: PMC3027850 DOI: 10.1016/j.acthis.2010.02.004] [Citation(s) in RCA: 306] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Revised: 02/14/2010] [Accepted: 02/16/2010] [Indexed: 12/18/2022]
Abstract
This review is intended for general readers who would like a basic foundation in carbohydrate structure and function, lectin biology, and the implications of glycobiology in human health and disease, particularly in cancer therapeutics. These topics are among the hundreds included in the field of glycobiology and are treated here because they form the cornerstone of glycobiology or the focus of many advances in this rapidly expanding field.
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Affiliation(s)
- Haike Ghazarian
- Department of Biology and Center for Cancer Developmental Biology, California State University Northridge, 18111 Nordhoff Street, Northridge, CA 91330-8303, USA
| | - Brian Idoni
- Department of Biology and Center for Cancer Developmental Biology, California State University Northridge, 18111 Nordhoff Street, Northridge, CA 91330-8303, USA
| | - Steven B. Oppenheimer
- Department of Biology and Center for Cancer Developmental Biology, California State University Northridge, 18111 Nordhoff Street, Northridge, CA 91330-8303, USA
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Kawasaki N, Kawasaki T. Recognition of Endogenous Ligands by C-Type Lectins:Interaction of Serum Mannan-binding Protein with Tumor-associated Oligosaccharide Epitopes. TRENDS GLYCOSCI GLYC 2010. [DOI: 10.4052/tigg.22.141] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Tateno H, Ohnishi K, Yabe R, Hayatsu N, Sato T, Takeya M, Narimatsu H, Hirabayashi J. Dual specificity of Langerin to sulfated and mannosylated glycans via a single C-type carbohydrate recognition domain. J Biol Chem 2009; 285:6390-400. [PMID: 20026605 DOI: 10.1074/jbc.m109.041863] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Langerin is categorized as a C-type lectin selectively expressed in Langerhans cells, playing roles in the first line of defense against pathogens and in Birbeck granule formation. Although these functions are thought to be exerted through glycan-binding activity of the C-type carbohydrate recognition domain, sugar-binding properties of Langerin have not been fully elucidated in relation to its biological functions. Here, we investigated the glycan-binding specificity of Langerin using comprehensive glycoconjugate microarray, quantitative frontal affinity chromatography, and conventional cell biological analyses. Langerin showed outstanding affinity to galactose-6-sulfated oligosaccharides, including keratan sulfate, while it preserved binding activity to mannose, as a common feature of the C-type lectins with an EPN motif. By a mutagenesis study, Lys-299 and Lys-313 were found to form extended binding sites for sulfated glycans. Consistent with the former observation, the sulfated Langerin ligands were found to be expressed in brain and spleen, where the transcript of keratan sulfate 6-O-sulfotransferase is expressed. Moreover, such sulfated ligands were up-regulated in glioblastoma relative to normal brain tissues, and Langerin-expressing cells were localized in malignant brain tissues. Langerin also recognized pathogenic fungi, such as Candida and Malassezia, expressing heavily mannosylated glycans. These observations provide strong evidence that Langerin mediates diverse functions on Langerhans cells through dual recognition of sulfated as well as mannosylated glycans by its uniquely evolved C-type carbohydrate-recognition domain.
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Affiliation(s)
- Hiroaki Tateno
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Central 2, 1-1-1 Umezono, Ibaraki 305-8568, Japan
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Nakamura N, Nonaka M, Ma BY, Matsumoto S, Kawasaki N, Asano S, Kawasaki T. Characterization of the interaction between serum mannan-binding protein and nucleic acid ligands. J Leukoc Biol 2009; 86:737-48. [DOI: 10.1189/jlb.1008674] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Powlesland AS, Hitchen PG, Parry S, Graham SA, Barrio MM, Elola MT, Mordoh J, Dell A, Drickamer K, Taylor ME. Targeted glycoproteomic identification of cancer cell glycosylation. Glycobiology 2009; 19:899-909. [PMID: 19433864 PMCID: PMC2704901 DOI: 10.1093/glycob/cwp065] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
GalMBP is a fragment of serum mannose-binding protein that has been modified to create a probe for galactose-containing ligands. Glycan array screening demonstrated that the carbohydrate-recognition domain of GalMBP selectively binds common groups of tumor-associated glycans, including Lewis-type structures and T antigen, suggesting that engineered glycan-binding proteins such as GalMBP represent novel tools for the characterization of glycoproteins bearing tumor-associated glycans. Blotting of cell extracts and membranes from MCF7 breast cancer cells with radiolabeled GalMBP was used to demonstrate that it binds to a selected set of high molecular weight glycoproteins that could be purified from MCF7 cells on an affinity column constructed with GalMBP. Proteomic and glycomic analysis of these glycoproteins by mass spectrometry showed that they are forms of CD98hc that bear glycans displaying heavily fucosylated termini, including Lewis(x) and Lewis(y) structures. The pool of ligands was found to include the target ligands for anti-CD15 antibodies, which are commonly used to detect Lewis(x) antigen on tumors, and for the endothelial scavenger receptor C-type lectin, which may be involved in tumor metastasis through interactions with this antigen. A survey of additional breast cancer cell lines reveals that there is wide variation in the types of glycosylation that lead to binding of GalMBP. Higher levels of binding are associated either with the presence of outer-arm fucosylated structures carried on a variety of different cell surface glycoproteins or with the presence of high levels of the mucin MUC1 bearing T antigen.
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Affiliation(s)
- Alex S Powlesland
- Division of Molecular Biosciences, Department of Life Sciences, Imperial College, London, UK
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Abstract
During last two decades, the chimerization and humanization of monoclonal antibodies (mAbs) have led to the approval of several for the treatment of cancer, autoimmune diseases, and transplant rejection. Additional approaches have been used to further improve their in vivo activity. These include combining them with other modalities such as chemotherapy and redesigning them for improved pharmacokinetics, effector function, and signaling activity. The latter has taken advantage of new insights emerging from an increased understanding of the cellular and molecular mechanisms that are involved in the interaction of immunoglobulin G with Fc receptors and complement as well as the negative signaling resulting from the hypercrosslinking of their target antigens. Hence, mAbs have been redesigned to include mutations in their Fc portions, thereby endowing them with enhanced or decreased effector functions and more desirable pharmacokinetic properties. Their valency has been increased to decrease their dissociation rate from cells and enhance their ability to induce apoptosis and cell cycle arrest. In this review we discuss these redesigned mAbs and current data concerning their evaluation both in vitro and in vivo.
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Affiliation(s)
- Xiao-yun Liu
- The Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8576, USA.
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Kawasaki N, Lin CW, Inoue R, Khoo KH, Kawasaki N, Ma BY, Oka S, Ishiguro M, Sawada T, Ishida H, Hashimoto T, Kawasaki T. Highly fucosylated N-glycan ligands for mannan-binding protein expressed specifically on CD26 (DPPVI) isolated from a human colorectal carcinoma cell line, SW1116. Glycobiology 2009; 19:437-50. [PMID: 19129245 DOI: 10.1093/glycob/cwn158] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The serum mannan-binding protein (MBP) is a host defense C-type lectin specific for mannose, N-acetylglucosamine, and fucose residues, and exhibits growth inhibitory activity toward human colorectal carcinoma cells. The MBP-ligand oligosaccharides (MLO) isolated from a human colorectal carcinoma cell line, SW1116, are large, multiantennary N-glycans with highly fucosylated polylactosamine-type structures having Le(b)-Le(a) or tandem repeats of the Le(a) structure at their nonreducing ends. In this study, we isolated the major MBP-ligand glycoproteins from SW1116 cell lysates with an MBP column and identified them as CD26/dipeptidyl peptidase IV (DPPIV) (110 kDa) and CD98 heavy chain (CD98hc)/4F2hc (82 kDa). Glycosidase digestion revealed that CD26 contained such complex-type N-glycans that appear to mediate the MBP binding. MALDI-MS of the N-glycans released from CD26 by PNGase F demonstrated conclusively that CD26 is the major MLO-carrying protein. More interestingly, a comparison of the N-glycans released from the MBP-binding and non-MBP-binding glycopeptides suggested that complex-type N-glycans carrying a minimum of 4 Le(a)/Le(b) epitopes arranged either as multimeric tandem repeats or terminal epitopes on multiantennary structures are critically important for the high affinity binding to MBP. Analysis of the N-glycan attachment sites demonstrated that the high affinity MLO was expressed preferentially at some N-glycosylation sites, but this site preference was not so stringent. Finally, hypothetical 3D models of tandem repeats of the Le(a) epitope and the MBP-Lewis oligosaccharide complex were presented.
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Affiliation(s)
- Nobuko Kawasaki
- Research Center for Glycobiotechnology, Ritsumeikan University, Shiga 525-8577, Japan
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Thiel S, Gadjeva M. Humoral pattern recognition molecules: mannan-binding lectin and ficolins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 653:58-73. [PMID: 19799112 DOI: 10.1007/978-1-4419-0901-5_5] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Innate immunity comprises a sophisticated network of molecules, which recognize pathogens, and effector molecules, working together to establish a quick and efficient immune response to infectious agents. Complement activation triggered by mannan binding lectin (MBL) or ficolins represents a beautiful example of this network Both MBL and ficolins recognize specific chemical structures on the surface of antigens and pathogens, thus bind to a broad variety of pathogens. Once bound further complement deposition is achieved through a cascade of proteolytic reactions. MBL and ficolin induced complement activation is critical for adequate anti-bacterial, anti-fungal and anti-viral responses. This is well illustrated by numerous and convincing studies that demonstrate associations between MBL deficiency and infections. Recent work has also highlighted that MBL and ficolins recognize self-structures, thus extending the role of these molecules beyond the traditional view of first line defense molecules. It appears that MBL deficiency may modulate the prognosis of inflammatory and autoimmune diseases. What is known about the mechanisms behind this broad scope of activities of MBL and ficolins is discussed in this chapter.
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Affiliation(s)
- Steffen Thiel
- Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark
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Polymorphisms of the mannan-binding lectin gene and systemic malignancies. Dig Dis Sci 2008; 53:3263. [PMID: 18465231 DOI: 10.1007/s10620-008-0307-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2008] [Accepted: 04/15/2008] [Indexed: 12/09/2022]
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Ishida YI, Yamashita K, Sasaki H, Takajou I, Kubuki Y, Morishita K, Tsubouchi H, Okayama A. Activation of complement system in adult T-cell leukemia (ATL) occurs mainly through lectin pathway: A serum proteomic approach using mass spectrometry. Cancer Lett 2008; 271:167-77. [DOI: 10.1016/j.canlet.2008.06.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2008] [Revised: 05/29/2008] [Accepted: 06/02/2008] [Indexed: 01/15/2023]
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Catano G, Agan BK, Kulkarni H, Telles V, Marconi VC, Dolan MJ, Ahuja SK. Independent effects of genetic variations in mannose-binding lectin influence the course of HIV disease: the advantage of heterozygosity for coding mutations. J Infect Dis 2008; 198:72-80. [PMID: 18498240 PMCID: PMC3777826 DOI: 10.1086/588712] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND The in vivo impact of mannose-binding lectin (MBL), a molecule involved in innate immunity, on the pathogenesis of human immunodeficiency virus (HIV)-1 infection and AIDS is unknown. METHODS A total of 1102 HIV-positive and 2213 HIV-negative adult subjects were screened for polymorphisms in the coding and promoter regions of MBL2, the gene that encodes MBL. RESULTS Variations in MBL2 did not influence the risk of acquiring HIV-1. Heterozygosity for coding mutations (O allele) and homozygosity for the -221 promoter polymorphism (X allele) in MBL2 were associated with a delay in and an accelerated rate of disease progression, respectively. MBL2 variations influenced the rate of progression to AIDS-defining illnesses. In a multivariate model, the effects of MBL2 variations were independent of several parameters known to influence disease progression, including steady-state viral load, baseline CD4(+) T cell counts, and delayed-type hypersensitivity skin test responses, an in vivo marker of cell-mediated immunity. The effects of MBL2 variations were most evident in those who possessed protective genotypes of CCR5 and a high copy number of CCL3L1, the most potent HIV-suppressive CCR5 ligand. CONCLUSIONS MBL2 genotypes are independent determinants of HIV disease progression and heterozygosity for MBL2 coding mutations confer disease-retarding effects. MBL-dependent immune responses may play a role in the pathogenesis of HIV infection.
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Affiliation(s)
- Gabriel Catano
- Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System and Department of Medicine, Texas
| | - Brian K. Agan
- Infectious Diseases Service, Texas
- Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, Texas
- San Antonio Military Medical Center, Fort Sam Houston, San Antonio, Texas
- Infectious Diseases Clinical Research Program, Uniformed Services University, Bethesda, Maryland
| | - Hemant Kulkarni
- Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System and Department of Medicine, Texas
| | - Vanessa Telles
- Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System and Department of Medicine, Texas
| | - Vincent C. Marconi
- Infectious Diseases Service, Texas
- San Antonio Military Medical Center, Fort Sam Houston, San Antonio, Texas
- Infectious Diseases Clinical Research Program, Uniformed Services University, Bethesda, Maryland
| | - Matthew J. Dolan
- Infectious Diseases Service, Texas
- Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, Texas
- San Antonio Military Medical Center, Fort Sam Houston, San Antonio, Texas
- Infectious Diseases Clinical Research Program, Uniformed Services University, Bethesda, Maryland
| | - Sunil K. Ahuja
- Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System and Department of Medicine, Texas
- Department of Microbiology, Immunology, and Biochemistry, University of Texas Health Science Center, Texas
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Wong JH, Chan HYE, Ng TB. A mannose/glucose-specific lectin from Chinese evergreen chinkapin (Castanopsis chinensis). Biochim Biophys Acta Gen Subj 2008; 1780:1017-22. [PMID: 18570898 DOI: 10.1016/j.bbagen.2008.05.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2007] [Revised: 05/22/2008] [Accepted: 05/22/2008] [Indexed: 10/22/2022]
Abstract
A mannose/glucose-specific lectin has been purified from Chinese evergreen chinkapin (Castanopsis chinensis) seeds, one of the most popular foods in East Asia. This lectin, designated as CCL, exhibited hemagglutinating activity in mouse and rabbit erythrocytes. It displayed a single band with a molecular mass of 29 kDa in SDS-PAGE and a 120-kDa peak in gel-filtration on Superdex-200. Its hemagglutinating activity was stable in the pH range 6-12 and at temperatures below 60 degrees C. The N-terminal amino acid sequence of CCL differed from those of other lectins in the same family. CCL inhibited the proliferation of HepG2 cells and adult emergence in fruitflies. CCL exhibited mitogenic activity toward mouse splenocytes, and induced nitric oxide production from mouse peritoneal macrophages but was devoid of inhibitory activity toward mycelial growth and HIV-1 reverse transcriptase.
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Affiliation(s)
- Jack H Wong
- Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong, China
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50
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Zheng P, Wang H, Zhao J, Song L, Qiu L, Dong C, Wang B, Gai Y, Mu C, Li C, Ni D, Xing K. A lectin (CfLec-2) aggregating Staphylococcus haemolyticus from scallop Chlamys farreri. FISH & SHELLFISH IMMUNOLOGY 2008; 24:286-293. [PMID: 18203621 DOI: 10.1016/j.fsi.2007.11.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2007] [Revised: 11/16/2007] [Accepted: 11/18/2007] [Indexed: 05/25/2023]
Abstract
Lectins are a family of carbohydrate-recognition proteins which play crucial roles in innate immunity. In this study, a new lectin (CfLec-2) gene was cloned from Chlamys farreri by EST and RACE approaches. The full-length cDNA of CfLec-2 was composed of 708bp, encoding a typical long form carbohydrate-recognition domain of 130 residues. The deduced amino acid sequence showed high similarity to Brevican in Homo sapiens, C-type lectin-1 and lectin-2 in Anguilla japonica. The cDNA fragment encoding the mature peptide of CfLec-2 was recombined into plasmid pET-32a (+) and expressed in Escherichia coli Rosseta-Gami (DE3). The recombinant CfLec-2 (rCfLec-2) protein exhibited aggregative activity toward Staphylococcus haemolyticus, and the agglutination could be inhibited by d-mannose but not EDTA or d-galactose, indicating that CfLec-2 was a Ca2+ independent lectin. Moreover, rCfLec-2 could suppress the growth of E. coli TOP10F'. These results suggested that CfLec-2 was perhaps involved in the recognition and clearance of bacterial pathogens in scallop.
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Affiliation(s)
- Peilin Zheng
- Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071, China
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