Exp Mol Med.  2013 Apr;45(4):e20.

MRP8 promotes Th17 differentiation via upregulation of IL-6 production by fibroblast-like synoviocytes in rheumatoid arthritis

• Lee DG
• Woo JW
• Kwok SK
• Cho ML
• Park SH

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.

Keyword

fibroblast-like synoviocytes; IL-6; MRP8; rheumatoid arthritis; Th17 differentiation

MeSH Terms

ATP-Binding Cassette Transporters/*metabolism
Adult
Aged
Arthritis, Rheumatoid/*pathology
CD4-Positive T-Lymphocytes/metabolism
Calgranulin B/metabolism
Cell Differentiation/*immunology
Fibroblasts/*metabolism/pathology
Humans
Inflammation Mediators/metabolism
Interleukin-17/metabolism
Interleukin-6/*biosynthesis
Middle Aged
Signal Transduction/immunology
Synovial Fluid/cytology
Synovial Membrane/metabolism/pathology
Th17 Cells/*pathology
Toll-Like Receptor 4/metabolism
*Up-Regulation
Calgranulin B
Inflammation Mediators
Interleukin-17
Interleukin-6
Toll-Like Receptor 4