Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis

Arthritis Rheum. 2006 Jan;54(1):158-68. doi: 10.1002/art.21537.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens
  • Arthritis / immunology*
  • Cytokines / biosynthesis*
  • Interleukin-6 / physiology*
  • Mice
  • Osteoclasts / physiology*
  • T-Lymphocytes / immunology*


  • Antigens
  • Cytokines
  • Interleukin-6