ATP suppression of interleukin-12 and tumour necrosis factor-alpha releasefrom macrophages

1 Immune cell activation releases ATP into the extracellular space. ATP-sen sitive P2 purinergic receptors are expressed on immune cells and activation of these receptors alters immune cell function. Furthermore, ATP is metabo lized by ectonucleotidases to adenosine, which has also been shown to alter cytokine production. In the present study, we investigated how extracellul ar ATP affects interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha p roduction in bacterial lipopolysaccharide (LPS)-treated murine peritoneal m acrophages and we also examined whether extracellular ATP alters the produc tion of the T helper 1 cytokine interferon (IFN)-gamma. 2 Pretreatment of the peritoneal macrophages with ATP or various ATP analog ues decreased both IL-12 and TNF-alpha production induced by LPS (10 mu g m l(-1)). The effect of ATP was partially reversed by cotreatment with adenos ine deaminase (0.1-1 u ml(-1)), suggesting that the suppressive effect of A TP on cytokine production is, in part, due to its degradation products. 3 Immunoneutralization with an anti-IL-10 antibody demonstrated that althou gh ATP increases IL-10 production, the inhibition of IL-12 and TNF-alpha pr oduction is independent of the increased IL-10. 4 The effect of ATP was pretranslational, as it suppressed steady state lev els of mRNAs for IL-12 (both p35 and p40). 5 In spleen cells stimulated with either LPS (10 mu g ml(-1)) or anti-CDS ( 2 mu g ml(-1)) antibody, ATP suppressed, in a concentration-dependent manne r, the production of IFN-gamma. 6 These results suggest that extracellular ATP has multiple anti-inflammatory effects and that release of ATP into the extracellular space may play a role in blunting the overactive immune resp onse in autoimmune diseases.