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MRP8 promotes Th17 differentiation via upregulation of IL-6 production by fibroblast-like synoviocytes in rheumatoid arthritis
Experimental & Molecular Medicine ; : e20-2013.
Article in English | WPRIM | ID: wpr-147328
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-kappaB 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.
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Full text: Available Index: WPRIM (Western Pacific) Main subject: Arthritis, Rheumatoid / Synovial Fluid / Synovial Membrane / CD4-Positive T-Lymphocytes / Signal Transduction / Cell Differentiation / Up-Regulation / Interleukin-6 / Inflammation Mediators / ATP-Binding Cassette Transporters Limits: Adult / Aged / Humans Language: English Journal: Experimental & Molecular Medicine Year: 2013 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Arthritis, Rheumatoid / Synovial Fluid / Synovial Membrane / CD4-Positive T-Lymphocytes / Signal Transduction / Cell Differentiation / Up-Regulation / Interleukin-6 / Inflammation Mediators / ATP-Binding Cassette Transporters Limits: Adult / Aged / Humans Language: English Journal: Experimental & Molecular Medicine Year: 2013 Type: Article