Emerging key roles for P2X receptors in the kidney.

Extracellular ATP serves as a danger signal to alert the immune system of tissue damage by acting on P2X or P2Y receptors. Here we show that allergen challenge causes acute accumulation of ATP in the airways of asthmatic subjects and mice with experimentally induced asthma. All the cardinal features of asthma, including eosinophilic airway inflammation, Th2 cytokine production and bronchial hyper-reactivity, were abrogated when lung ATP levels were locally neutralized using apyrase or when mice were treated with broad-spectrum P2-receptor antagonists. In addition to these effects of ATP in established inflammation, Th2 sensitization to inhaled antigen was enhanced by endogenous or exogenous ATP. The adjuvant effects of ATP were due to the recruitment and activation of lung myeloid dendritic cells that induced Th2 responses in the mediastinal nodes. Together these data show that purinergic signaling has a key role in allergen-driven lung inflammation that is likely to be amenable to therapeutic intervention.

This review is aimed at providing readers with a comprehensive reference article about the distribution and function of P2 receptors in all the organs, tissues, and cells in the body. Each section provides an account of the early history of purinergic signaling in the organ?cell up to 1994, then summarizes subsequent evidence for the presence of P2X and P2Y receptor subtype mRNA and proteins as well as functional data, all fully referenced. A section is included describing the plasticity of expression of P2 receptors during development and aging as well as in various pathophysiological conditions. Finally, there is some discussion of possible future developments in the purinergic signaling field.

Extracellular ATP (ATPe) is known to cause release of processed IL-1 beta from LPS-treated macrophages and microglial cells. IL-1 beta release is fast and thought to be associated with cell death. We have reinvestigated this process to identify 1) the purinergic receptor involved; 2) the relationship to cell death; and 3) pharmacologic agonists or antagonists able to modulate IL-1 beta release. Our data confirm that ATPe is a powerful stimulus for IL-1 beta release from LPS-treated human macrophages; however, we also show that IL-1 beta release is not necessarily associated with cell death, as it occurs at lower ATP concentrations and much earlier than leakage of cytoplasmic markers. The selective purinergic P2Z receptor agonist benzoylbenzoyl ATP was at least one order of magnitude more powerful than ATP, but also had a strong cytotoxic effect. 2-Methylthio-ATP was equipotent as ATPe at the optimal concentration of 1 mM, but markedly inhibitory at higher concentrations. The irreversible P2Z blocker-oxidized ATP completely inhibited ATPe-induced IL-1 beta release. IL-1 beta release also was inhibited by increasing the K+ concentration of the incubation medium. These data suggest that ATPe triggers IL-1 beta via the purinergic P2Z receptor recently shown to be expressed by human macrophages and identified as a new member of the P2X family (P2X7), and provide pharmacologic tools for the modulation of IL-1 beta release in vitro and, possibly, in vivo.