P2 receptor blockade attenuates fever and cytokine responses induced by lipopolysaccharide in rats

Adenosine 5′‐triphosphate (ATP) has been shown to induce release of cytokines implicated in fever, including interleukin(IL)‐1β, IL‐6, and tumour necrosis factor‐α (TNF‐α). The role of ATP‐mediated purinergic signalling in fever and cytokine release during systemic inflammation was investigated by studying the effects of P2 receptor antagonists suramin, pyridoxal‐5′‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS), and Brilliant Blue G (BBG) on changes in body temperature and the increases in plasma levels of IL‐1β, IL‐6, and TNFα induced by bacterial lipopolysaccharide (LPS) in rats. LPS (Escherichia coli; 50 μg kg−1)‐induced febrile response was attenuated by suramin (25 mg kg−1 and 100 mg kg−1), PPADS (25 mg kg−1), and a more selective P2X7 receptor antagonist BBG (100 mg kg−1) injected intraperitoneally before the induction of fever. The increase in plasma concentrations of IL‐1β and IL‐6, measured 1 h after LPS treatment, was reduced by PPADS (25 mg kg−1) and BBG (100 mg kg−1). LPS‐induced increase in plasma TNF‐α concentration was also markedly attenuated by BBG (100 mg kg−1), but not by PPADS (25 mg kg−1). These data indicate that purinergic signalling plays an important role in the mechanisms responsible for the LPS‐induced febrile response and increases in the levels of circulating cytokines. We suggest that ATP acting via P2X7 receptors induces release of pyrogenic cytokines to mediate fever during systemic inflammation. British Journal of Pharmacology (2005) 146, 139–145. doi:10.1038/sj.bjp.0706287