Activation of adenosine receptors inhibits tumor necrosis factor-alpha release by decreasing TNF-alpha mRNA stability and p38 activity.
Adenosine receptor agonists have anti-inflammatory properties and modulate immune responses partly by inhibiting pro-inflammatory cytokine production by monocytes. We investigated signal transduction mechanisms by which adenosine receptor activation inhibits tumor necrosis factor-alpha (TNF-alpha) production. Phorbol-12-myristate-13-acetate (PMA) and phytohemagglutinin treatment of human pro-monocytic U937 cells increased TNF-alpha protein release. Activation of adenosine receptors up to 1 hr following stimulation with PMA/phytohemagglutinin significantly inhibited TNF-alpha protein release indicating that inhibition of TNF-alpha occurred post-transcriptionally. The adenosine receptor agonist 2-p-(carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) decreased stability and half-life of PMA/phytohemagglutinin-induced TNF-alpha mRNA from 80 to 37 min. p38 signaling pathways control TNF-alpha mRNA stability in macrophages and we confirmed in our cells that p38 was involved in controlling TNF-alpha release post-transcriptionally. Activation of adenosine receptors with CGS 21680 decreased phospho-p38 protein levels. These data suggest that adenosine receptor activation regulates TNF-alpha release post-transcriptionally by decreasing mRNA stability through a mechanism involving inhibition of p38 activity.
Department of Pharmacology and Therapeutics, University of Manitoba, Faculty of Medicine, Division of Neuroscience Research, St. Boniface Hospital Research Centre, R4046-351 Tache Ave., Winnipeg, Manitoba R2H 2A6, Canada.
Julie A
JA
Fotheringham
Michael B
MB
Mayne
Jeffrey A
JA
Grant
Jonathan D
JD
Geiger
D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D014176:Protein Biosynthesis; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
D010835:Phytohemagglutinins; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C016658:phorbolol myristate acetate; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate