Dysregulated cytokine production, in particular of the monokines IL-1, IL-6, and TNF, has been implicated in the inflammatory response in rheumatoid arthritis and in promoting the ensuing tissue destruction. The 3-substituted 2-oxindole tenidap has proven anti-inflammatory actions both in vivo and in vitro, among which is the inhibition of TNF and IL-1 production by monocytes following activation by LPS. We have investigated this ability to modulate cytokine activity by studying its effects on cytokine-monocyte interactions and in particular IL-6 production, with the THP-1 monocyte cell line. Tenidap inhibited IL-6 production in a dose-dependent manner when cells were stimulated with a combination of TNF-alpha and IFN-gamma. It also inhibited the priming effect of IFN-gamma, preventing the super-induction of IL-6 production following subsequent stimulation with TNF-alpha and IFN-gamma. These effects occurred under conditions in which the cells were not irreversibly altered with respect to their protein synthetic activity. IFN-gamma-induced up-regulation of HLA-DR was also inhibited by tenidap. Tenidap appears to affect some aspect of the IFN-gamma activation pathway, possibly the differentiation of these immature monocytes to a more mature phenotype. The data presented here indicate that tenidap has the potential to modulate the cytokine network in chronic disease.

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