Arthritogenic actions of recombinant IL-1 and tumour necrosis factor α in the rabbit: evidence for synergistic interactions between cytokines in vivo

Intra-articular injection of highly purified or recombinant interleukin 1 (IL-1) into the rabbit knee induces a transient synovitis with leucocytic infiltration into the synovial lining and joint cavity and loss of proteoglycan from articular cartilage. Tumour necrosis factor alpha (TNF-alpha), which has many of the actions of IL-1, in the dose range 50-5,000 ng induced infiltration of leucocytes into the joint but failed to cause significant proteoglycan loss from cartilage. The nature of the leucocytic infiltrate induced by intra-articular TNF-alpha was predominantly monocytic compared with the mixed polymorphonuclear (PMN)/monocytic infiltrate induced by IL-1. Neither cytokine induced the accumulation of significant numbers of lymphocytes. In addition, on a molar basis, TNF-alpha was significantly less active than IL-1 in causing cell accumulation in the joint. Injection of submaximal doses of IL-1 and TNF into the rabbit resulted in a marked synergy with respect to the accumulation of PMN. The conclusion from these studies is that TNF-alpha could contribute to the PMN accumulation in the human joint in rheumatoid arthritis but is unlikely to be important in the destruction of articular cartilage.