CYTOKINE STIMULATION OF T-LYMPHOCYTES REGULATES THEIR CAPACITY TO INDUCE MONOCYTE PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA, BUT NOT INTERLEUKIN-10 - POSSIBLE RELEVANCE TO PATHOPHYSIOLOGY OF RHEUMATOID-ARTHRITIS

Previous studies in the laboratory have shown that the pro-inflammator y cytokine tumor necrosis factor (TNF)-alpha plays a pivotal role in t he pathogenesis of rheumatoid arthritis (RA). The mechanisms involved in regulating monocyte/macrophage cytokine production are not yet full y understood, but are thought to involve both soluble factors and cell /cell contact with other cell types. We and others have previously dem onstrated that T cells activated through the T cell receptor/CD3 compl ex induce monocyte TNF-alpha production by contact-mediated signals. I n this report, we investigated further whether T cells activated by cy tokines in the absence of T cell receptor stimulation also regulate mo nocyte cytokine production. T cells were activated in an antigen-indep endent manner using the cytokines interleukin (IL)-15 or IL-2 alone, o r in combination with IL-6 and TNF-alpha. Subsequently, T cells were f ixed and incubated with monocytes. Fixed, cytokine-stimulated T cells induced monocytes to secrete TNF-alpha in a dose-dependent manner, but did not induce secretion of IL-10, a potent endogenous down-regulator of TNF-alpha and other pro-inflammatory cytokines. Stimulation of mon ocyte TNF-alpha was markedly inhibited when T cells were physically se parated from monocytes within the tissue culture well, confirming that T cell contact is necessary. T cell acquisition of monocyte-activatin g capacity was shown to be dependent on the period of cytokine stimula tion, with T cells activated for 8 days more effective than T cells ac tivated for shorter periods. Addition of interferon-gamma or granulocy te/macrophage colony-stimulating factor to the T cell/monocyte culture s enhanced T cell induction of monocyte TNF-alpha by threefold and nin efold, respectively The results from this model of cognate interaction suggest that cytokine-stimulated T cells, interacting with macrophage s in the rheumatoid synovial membrane, may contribute to the continuou s excessive production of TNF-alpha observed in the RA joint, and to t he imbalance of pro-inflammatory cytokines over anti-inflammatory cyto kines.