Signaling in lipopolysaccharide-induced stabilization of formyl peptide receptor 1 mRNA in mouse peritoneal macrophages.
To identify the TLR4-initiated signaling events that couple to formyl peptide receptor (FPR)1 mRNA stabilization, macrophages were treated with LPS along with a selection of compounds targeting several known signaling pathways. Although inhibitors of protein tyrosine kinases, MAPKs, and stress-activated kinases had little or no effect on the response to LPS, LY294002 (LY2) and parthenolide (an IkappaB kinase inhibitor) were both potent inhibitors. LY2 but not parthenolide blocked the LPS-induced stabilization of FPR1 mRNA. Although both LY2 and wortmannin effectively blocked PI3K activity, wortmannin had little effect on FPR1 expression and did not modulate the decay of FPR1 mRNA. Moreover, although LY2 was demonstrated to be a potent inhibitor of PI3K activity, a structural analog of LY2, LY303511 (LY3), which did not inhibit PI3K, was equally effective at preventing LPS-stimulated FPR1 expression. The mammalian target of rapamycin activity (measured as phospho-p70S6 kinase) was activated by LPS but not significantly blocked by LY2. In addition, although rapamycin blocked mTOR activity, it did not inhibit FPR1 mRNA expression. Finally, the mechanisms involved in stabilization of FPR1 by LPS could be distinguished from those involved in stabilization of AU-rich mRNAs because the prolonged half-life of FPR1 mRNA was insensitive to the inhibition of p38 MAPK. These findings demonstrate that LY2/LY3 targets a novel TLR4-linked signaling pathway that selectively couples to the stabilization of FPR1 mRNA.
Mandal
Palash
P
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Hamilton
Thomas
T
D020413:3' Untranslated Regions / Q000276:immunology / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects* / Q000276:immunology; D012333:RNA, Messenger / Q000276:immunology* / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis / Q000276:immunology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
D020413:3' Untranslated Regions; D000730:Androstadienes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002867:Chromones; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D012717:Sesquiterpenes; D058570:TOR Serine-Threonine Kinases; D051197:Toll-Like Receptor 4; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C469988:Fpr1 protein, mouse; C493487:Tlr4 protein, mouse; C093555:LY 303511; C002669:parthenolide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546843:mTOR protein, mouse