Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis
Details
Publication Year 2006-01,Volume 54,Issue #1,Page 158-168
Journal Title
ARTHRITIS AND RHEUMATISM
Publication Type
Journal Article
Abstract
Objective. To determine the cellular mediators of antigen-induced arthritis (AIA) and the relative contribution of members of the interleukin-6 (IL-6) family and tumor necrosis factor (TNF) in AIA. Methods. AIA was induced in mice deficient in T and B lymphocytes, IL-6 (IL-6(-/-)), TNF (TNF-/-), IL-11 receptor, and oncostatin M receptor, by immunization with methylated bovine serum albumin (mBSA) followed 7 days later by intraarticular injection of mBSA. Arthritis severity was assessed histologically, and T lymphocyte responses were assessed in vitro. Anti-TNF neutralizing antibody was administered to wild-type mice during AIA. Bone marrow osteoclasts were generated in vitro via culture with RANKL and macrophage colony-stimulating factor. Results. AIA was dependent on CD4+ T lymphocytes, but not CD8+ T lymphocytes or B cells. IL-6(-/-) mice had reduced AIA severity and fewer osteoclasts at sites of bone erosion. This protective effect was not seen with a deficiency of other IL-6 family members and was similar to that in TNF-/- mice or wild-type mice receiving TNF blockade treatment. IL-6(-/-) CD4+ T lymphocytes from draining lymph nodes had reduced antigen-induced proliferation and produced less IL-17 and less RANKL, relative to osteoprotegerin, than cells from wild-type mice. Bone marrow from IL-6(-/-) mice generated fewer osteoclasts in vitro than bone marrow from either wild-type or TNF-/- mice. Conclusion. AIA is driven by CD4+ T lymphocytes. IL-6 is an important mediator of bone destruction in AIA because it regulates T lymphocyte production of key osteoclastogenic cytokines and inflammation-induced bone marrow osteoclast differentiation. These findings have implications for reducing bone and joint damage in rheumatoid arthritis.
Publisher
WILEY-LISS
Keywords
NF-KAPPA-B; MONOCLONAL-ANTIBODY TREATMENT; COLLAGEN-INDUCED ARTHRITIS; LEUKEMIA INHIBITORY FACTOR; NECROSIS-FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; RECEPTOR ACTIVATOR; BONE-RESORPTION; ONCOSTATIN-M; OSTEOPROTEGERIN LIGAND
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Creation Date: 2006-01-01 12:00:00
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