Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes.
Regulation of P2X7 receptor expression is of interest because activation of this receptor by extracellular ATP triggers maturation and release of the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) in monocytes and macrophages. We report that interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synergistically induce P2X7R mRNA and functional responses in the human THP-1 monocytic cell line. Induction was dose dependent, with maximal functional activity requiring 1000 units/mL IFN-gamma and 10 ng/mL TNF-alpha and incubations of 36-72 h. The up-regulation of P2X7R function by lipopolysaccharide (LPS)/IFN-gamma and TNF-alpha/IFN-gamma was markedly attenuated by coincubation with prostaglandin E2 or the cell permeant cyclic AMP analog dibutryl cAMP (Bt2cAMP). Bt2cAMP did not significantly alter P2X7 function in HEK-293 cells stably transfected with the human P2X7 cDNA, indicating that Bt2cAMP does not exert a generalized effect on P2X7R synthesis or downstream signal transduction. These studies demonstrate that elevated cAMP negatively modulates P2X7R expression.
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
B D
BD
Humphreys
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Dubyak
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000345:Affinity Labels / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000276:immunology; D058486:Receptors, Purinergic P2X7; D015290:Second Messenger Systems / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000345:Affinity Labels; D002273:Carcinogens; D007375:Interleukin-1; C546468:P2RX7 protein, human; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D003994:Bucladesine; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate