2--3--dialdehyde-atp and Inflammation

Activation of P2X7 receptors by endogenous ATP contributes to the development of inflammatory hyperalgesia. Given the clinical importance of mechanical hyperalgesia in inflammatory states, we hypothesized that the activation of the P2X7 receptor by endogenous ATP contributes to carrageenan-induced mechanical hyperalgesia, and that this contribution is mediated by an indirect sensitization of the primary afferent nociceptors. Co-administration of the selective P2X7 receptor antagonist, A-438079, or the P2X7 receptor antagonist, oATP, with carrageenan blocked the mechanical hyperalgesia induced by carrageenan and significantly reduced the increased concentration of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta induced by carrageenan in the subcutaneous tissue of the rat's hind paw. We concluded that the activation of P2X7 receptors by endogenous ATP is essential to the development of the mechanical hyperalgesia induced by carrageenan in the subcutaneous tissue. It is suggested that this essential role of P2X7 receptors in the development of carrageenan-induced mechanical hyperalgesia is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta.

Topics: Adenosine Triphosphate; Animals; Carrageenan; Chemokine CXCL1; Disease Models, Animal; Hyperalgesia; Inflammation; Interleukin-6; Male; Pyridines; Rats; Rats, Wistar; Receptors, Purinergic P2X7; Tetrazoles; Tumor Necrosis Factor-alpha

T cell receptor (TCR) stimulation results in the influx of Ca(2+), which is buffered by mitochondria and promotes adenosine triphosphate (ATP) synthesis. We found that ATP released from activated T cells through pannexin-1 hemichannels activated purinergic P2X receptors (P2XRs) to sustain mitogen-activated protein kinase (MAPK) signaling. P2XR antagonists, such as oxidized ATP (oATP), blunted MAPK activation in stimulated T cells, but did not affect the nuclear translocation of the transcription factor nuclear factor of activated T cells, thus promoting T cell anergy. In vivo administration of oATP blocked the onset of diabetes mediated by anti-islet TCR transgenic T cells and impaired the development of colitogenic T cells in inflammatory bowel disease. Thus, pharmacological inhibition of ATP release and signaling could be beneficial in treating T cell-mediated inflammatory diseases.

Topics: Active Transport, Cell Nucleus; Adenosine Triphosphate; Animals; Autocrine Communication; Calcium; Cell Nucleus; Cell Proliferation; Connexins; Cyclic AMP; Inflammation; Interleukin-2; Lymphocyte Activation; MAP Kinase Signaling System; Mice; Mice, Knockout; Mice, Mutant Strains; Nerve Tissue Proteins; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Signal Transduction; T-Lymphocytes

Periodate-oxidized ATP (oATP), which covalently modifies nucleotide-binding proteins, can significantly attenuate proinflammatory signaling. Although the P2X7 nucleotide receptor (P2X7R) is irreversibly antagonized by oATP, it is unclear whether anti-inflammatory actions of oATP are predominantly mediated via its actions on P2X7R. Here, we describe inhibitory effects of oATP on proinflammatory responses in three human cell types that lack expression of P2X7R: human umbilical vein endothelial cells (HUVEC), HEK293 cells, and 1321N1 astrocytes. oATP decreased by 40-70% the secretion of interleukin (IL)-8 stimulated by tumor necrosis factor-alpha (TNF-alpha) in all three cell types, by IL-1beta in HUVEC and 1321N1 cells, and by endotoxin in HUVEC. Attenuation of TNF-alpha-stimulated IL-8 secretion by oATP was similar in wild-type HEK cells or HEK cells stably expressing recombinant P2X7R. oATP also attenuated cytokine-stimulated expression of nuclear factor-kappaB-luciferase reporter genes expressed in HEK or 1321N1 cells, but did not affect the rapid downregulation of IkappaB. oATP had no effect on uridine triphosphate-induced activation of native P2Y2 receptors in HEK cells, but reduced the potency and efficacy of ADP as an agonist of native P2Y1 receptors. However, inhibition of P2Y1 receptors with the specific antagonist MRS2216 did not mimic the effects of oATP on TNF-alpha-stimulated IL-8 secretion. Although 1321N1 astrocytes lack expression of any known P2 receptor subtypes, oATP markedly inhibited ecto-ATPase activity in these cells, resulting in a significant accumulation of extracellular ATP. In summary, oATP can attenuate proinflammatory signaling by mechanisms independent of the expression or activation of known P2 receptor subtypes.

Topics: Adenosine Triphosphate; Cell Line; Cell Line, Tumor; Cytokines; Humans; Inflammation; Inflammation Mediators; Oxidation-Reduction; Purinergic P2 Receptor Agonists; Receptors, Purinergic P2; Signal Transduction