Purinergic receptor regulation of LPS-induced signaling and pathophysiology.
Macrophages express several lipopolysaccharide (LPS) binding proteins and are potently activated by LPS to produce inflammatory mediators. Recent studies have shown that receptors for exogenous nucleotides (P2X and P2Y purinergic receptors) can modulate macrophage production of TNF-alpha, IL-1beta and nitric oxide (NO) following LPS exposure. Macrophages and LPS-stimulated monocytes express elevated levels of P2Y1, P2Y2 and P2X7 mRNA, suggesting that both P2Y and P2X receptors can contribute to LPS-induced pathophysiology. In addition, oxidized-ATP treatment (which inhibits P2X7) of macrophages blocks LPS-induced NO production, NF-kappaB and ERK-1/2 activation. Also, an LPS-binding domain located in the P2X7 C-terminus appears important for receptor trafficking/function. Moreover, the purinergic receptor ligand 2-MeS-ATP attenuates LPS-induced cytokine and NO production in vivo and ex vivo. These data suggest that P2X7 and certain P2Ys are linked to LPS effects, although their relative contribution in vivo is unclear. Accordingly, we tested the capacity of several adenine nucleotides to modulate LPS-induced mortality in mice. We found that the P2X7-directed ligand BzATP was unable to prevent LPS-induced death, whereas 2-MeS-ATP and 2-Cl-ATP, which bind to multiple P2X and P2Y receptors were able to protect mice from LPS-induced death. These data suggest that the co-ordinate action of P2Y and P2X7 receptors are critical for controlling LPS responses in vivo and that agents directed against both receptor classes may provide the greatest therapeutic advantage.
Guerra
Alma N
AN
Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, WI 53706-1532, USA.
Fisette
Philip L
PL
Pfeiffer
Zachary A
ZA
Quinchia-Rios
Beatriz H
BH
Prabhu
Usha
U
Aga
Mini
M
Denlinger
Loren C
LC
Guadarrama
Arturo G
AG
Abozeid
Sara
S
Sommer
Julie A
JA
Proctor
Richard A
RA
Bertics
Paul J
PJ
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011485:Protein Binding; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D012772:Shock, Septic / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D008024:Ligands; D008070:Lipopolysaccharides; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse