Arthritis induced by interleukin-1 is dependent on the site and frequency of intraarticular injection.

Intraarticular injection of recombinant human interleukin-1 (IL-1) in rats resulted in varying degrees of inflammatory changes depending on the site and frequency of injections. (i) Much lower amounts of IL-1 were required to elicit an inflammatory response in the ankle joints (15-3000 ng) than the knee joints (90-150 micrograms). (ii) The inflammatory response was much greater if IL-1 was administered in multiple doses as compared to a single dose injection. One day after a single injection of IL-1 (90-150 micrograms), knee joints exhibited a mild increase in volume as a consequence of edema, but at the end of 1 week, no discernible change in volume was observed. However, when the same total amount of IL-1 was injected in three doses, there was a dramatic increase in joint volume at the end of 1 week that persisted for at least 3 weeks. The increase was dose dependent. (iii) The inflammatory response was dependent on the age/weight of the rats: the older the animals the greater the response. (iv) Under conditions where IL-1 induced inflammatory changes in knee joints, recombinant tumor necrosis factor failed to induce any significant response. (v) Histological examination of the knee joints revealed distinct differences in the pathological response to the two different protocols of IL-1 administration in the knee joints. The animals injected with a single dose of IL-1 showed a mild and transient inflammation that was resolved by 2 weeks postinjection, but exhibited degenerative changes associated with focal loss of chondrocytes and proteoglycan of the knee joint cartilage, which became progressively severe. The knee joints of animals given three injections of IL-1 showed evidence of marked acute synovitis, fibroplasia, loss of proteoglycan and chondrocytes, resorption of subchondral bone, and transition of hematopoeitic marrow cells into cells of mesenchymal morphology. (vi) Examination of proteoglycan synthesis by cartilage of IL-1-injected rats revealed that within 1 day after injection, a dramatic reduction in synthesis occurred which persisted for at least 2 weeks. These studies suggest that intraarticular injection of IL-1 provides a useful rodent model for the investigation of pathological changes occurring within a localized joint as a result of acute and chronic inflammatory stimuli. Relevant aspects of the pathology of joint erosion can be demonstrated depending on the frequency of IL-1 injection.