title: MRP8 promotes Th17 differentiation via upregulation of IL-6 production by fibroblast-like synoviocytes in rheumatoid arthritis.
abstract: Myeloid-related protein (MRP)8/MRP14 is an endogenous Toll-like receptor 4 (TLR4) ligand and is abundant in synovial fluid (SF) of rheumatoid arthritis (RA) patients. Belonging to damage-associated molecular patterns, it amplifies proinflammatory mediators and facilitates a wide range of inflammatory and autoimmune diseases. Interleukin (IL)-17-producing T-helper (Th)17 cells have a crucial role in RA pathogenesis, and IL-6 is the key factor promoting Th17 differentiation. We investigated whether the level of MRP8/MRP14 is positively associated with IL-6 and IL-17 levels in RA SF and found that MRP8/MRP14 level had a significant correlation with IL-6 and IL-17 levels in RA SF. We also observed that MRP8-induced IL-17 production by peripheral blood mononuclear cells but MRP14 did not. Upon stimulation with MRP8, IL-6 production was enhanced by RA fibroblast-like synoviocytes (FLS) and was further elevated by coculturing RA FLS with activated CD4+ T cells. Moreover, we demonstrated that MRP8-activated IL-6 production by RA FLS promoted differentiation of Th17 cells using the coculture system consisting of CD4+ T cells and RA FLS. In addition, IL-6 blockade attenuated Th17 polarization of CD4+ T cells in the cocultures. Inhibitor studies revealed that MRP8 increased IL-6 production in RA FLS via TLR4/phosphoinositide 3-kinase/nuclear factor-κB and mitogen-activated protein kinase signaling pathways. Our results show that MRP8 has a crucial role in stimulating IL-6 expression by RA FLS, and subsequently promotes Th17 differentiation in RA, suggesting that neutralizing MRP8 level in RA synovium may be an effective therapeutic strategy in RA treatment.
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong-Gun
authors.initials: DG
authors.lastname: Lee
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Woo
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D008875:Middle Aged; D015398:Signal Transduction / Q000276:immunology; D013582:Synovial Fluid / Q000166:cytology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; C508600:IL6 protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4