Using
interleukin (IL)-6-deficient (IL-6(0/0) mice or wild-type mice, we investigated the controversial role of IL-6 in joint
inflammation and cartilage pathology during
zymosan-induced
arthritis (ZIA). Monoarticular
arthritis was elicited by injection of
zymosan into the right knee joint cavity. Production of IL-1,
tumor necrosis factor (TNF), IL-6, and
nitric oxide by the inflamed knee was assessed in washouts of joint capsule specimens. Plasma
corticosterone was measured using a radioimmunoassay.
Proteoglycan synthesis was assessed using [35S]
sulfate incorporation into patellas ex vivo. Joint swelling was quantified by joint uptake of circulating 99mTechnetium
pertechnetate. Histology was taken to evaluate cellular infiltration and cartilage damage.
Zymosan caused a rapid increase in articular IL-1, IL-6, TNF, and NO levels. Except for IL-6, the released amounts and time course of these mediators were comparable in the IL-6-deficient mice and the wild-type mice. Elevated plasma
corticosterone levels were measured during the first day of
arthritis in both strains. At day 2 of ZIA, joint
inflammation (joint swelling and cell exudate) in IL-6-deficient mice was comparable with that in the wild-type mice. The marked suppression of chondrocyte
proteoglycan synthesis and
proteoglycan degradation were on the average higher in the IL-6-deficient mice. Together this resulted in a more pronounced
proteoglycan depletion in the IL-6-deficient mice as compared with the wild-type mice during the first week of
arthritis. Injection of recombinant IL-6 into the joint cavity corrected the IL-6 deficiency and significantly reduced cartilage destruction.
Inflammation was more chronic in the wild-type mice, and these mice also showed a higher prevalence for
osteophyte formation. In ZIA, IL-6 plays a dual role in connective tissue pathology, reducing
proteoglycan loss in the acute phase and enhancing
osteophyte formation in the chronic phase. The latter could be related to the more severe joint
inflammation as seen in the normal (IL-6-producing) animals during the chronic phase of
arthritis.