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(American Journal of Pathology. 2000;157:2081-2091.)
© 2000 American Society for Investigative Pathology

Regular Articles

Involvement of IL-6, Apart from Its Role in Immunity, in Mediating a Chronic Response during Experimental Arthritis

From the Rheumatology Research Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands

Interleukin-6 (IL-6) is highly produced during arthritis but its exact function is still unknown. In this study we examined if IL-6, apart from its role in immunity, was involved in the local inflammatory response in experimental arthritis. IL-6 deficient (IL-6^-/-) and wild-type mice were first compared in the antigen-induced arthritis model. IL-6 deficiency resulted in a mild, transient inflammation whereas wild-type mice developed a chronic, destructive synovitis. Wild-type mice immunized with one-tenth of the normal antigen dose still developed chronic arthritis despite low antibody levels, excluding reduced humoral immunity in IL-6^-/- mice as a crucial phenomenon. In addition, passive immune-complex-induced arthritis did not differ between wild-type and IL-6^-/- mice. Another option is reduced levels of Th1 cells in IL-6^-/- mice. However, transfer of antigen-specific wild-type lymph node cells to IL-6^-/- mice enhanced acute joint inflammation and increased cartilage damage but still could not sustain chronic inflammation, suggesting involvement of nonimmune elements of IL-6 activity in chronicity. In line with this, nonimmunologically mediated zymosan-induced arthritis developed similarly in the first week, but only wild-type mice developed chronic synovitis. These results indicate an important role for IL-6 in propagation of joint inflammation, potentially independent of its role in immunity.

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