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


CONCLUSIONS
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.
Wong
Peter K K
PK
Division of Autoimmunity and Transplantation, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Quinn
Julian M W
JM
Sims
Natalie A
NA
van Nieuwenhuijze
Annemarie
A
Campbell
Ian K
IK
Wicks
Ian P
IP
D000818:Animals; D000941:Antigens; D001168:Arthritis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D010010:Osteoclasts / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D016207:Cytokines; D015850:Interleukin-6