INDUCTION OF ENHANCED RESPONSIVENESS OF HUMAN ARTICULAR CHONDROCYTES TO EXTRACELLULAR ATP BY TUMOR-NECROSIS-FACTOR-ALPHA

1. We have observed previously that extracellular ATP acting at P2-purinoceptors promotes the production of prostaglandin E2 by human articular chondrocytes, and that this response is enhanced synergistically by interleukin-1beta. Since other cytokines that influence the metabolism of articular cartilage may have a similar effect, we have investigated whether tumour necrosis factor-alpha also modulates the stimulation of the production of prostaglandin E2 in these cells by ATP. 2. Tumour necrosis factor-alpha enhanced the response of cultured human articular chrondrocytes to a maximally stimulating concentration of ATP (100 mumol/l). This effect was present when the cells were co-incubated with tumour necrosis factor-alpha and ATP for 4 h, was augmented when the cells were also preincubated with the cytokine for 24 h, and remained constant or declined on extending the preincubation period to 72h. The enhancement of responsiveness to ATP by tumour necrosis factor-alpha was dose-dependent, and the minimum effective concentration (6 pmol/l) did not consistently increase prostaglandin E2 production when the cytokine was tested alone. The presence of tumour necrosis factor-alpha during the incubation with ATP was required for maximum enhancement of the response. Tumour necrosis factor-alpha did not alter the minimum concentration of ATP that stimulated production of prostaglandin E2. 3. Cytokines such as interleukin-1 and tumour necrosis factor-alpha are involved in the pathogenesis of some forms of arthritis, and these data provide additional evidence that their actions in articular cartilage may be modulated by other agents which originate from chondrocytes. Moreover, although both these cytokines enhance responsiveness of human articular chondrocytes to extracellular ATP, differences in their effects were observed which suggest that they may act independently.