P2X7 nucleotide receptor: Modulation of LPS‐induced macrophage signaling and mediator production

Abstract

AbstractDuring infection or inflammation, high concentrations of extracellular nucleotides are released into the inflammatory microenvironment, supplying a source of ligand for purinergic receptors that are present on many immune cell types. The P2X7 receptor, a member of the P2X purinergic receptor family of ATP‐gated ion channels, is thought to play an important role in monocyte/macrophage activation. One factor that can powerfully activate macrophages is bacterial lipopolysaccharide (endotoxin, LPS) and although the mechanisms involved in this process are not well understood, it is clear that LPS activation of macrophages is central to the development of septic shock in response to Gram‐negative bacteria. Several lines of evidence have demonstrated strong modulatory effects of adenine nucleotides on the events associated with LPS stimulation of macrophages. Further, because the signal transduction cascades initiated in macrophages upon LPS exposure are similar to those resulting from P2X7 receptor stimulation, and because antagonism of the P2X7 receptor can attenuate LPS‐stimulated signaling events and mediator release, the P2X7 receptor has been implicated in the control of macrophage responses to LPS. In addition, our laboratory has identified a consensus LPS‐binding motif at the extreme carboxyl terminus of the P2X7 receptor, further supporting the potential for a direct interaction between LPS and this purinergic receptor. In this review, we discuss potential regulatory domains and structural features of the P2X7 receptor and outline some of the signal transduction pathways activated by P2X7 receptor agonists. Moreover, we present evidence supporting a critical role for the P2X7 receptor in modulating or mediating some of the biological effects of LPS in macrophages. Drug Dev. Res. 53:91–104, 2001. © 2001 Wiley‐Liss, Inc.