Multiple signaling cascades are differentially involved in gene induction by double stranded RNA in interferon-alpha-primed cells.
Priming with interfon (IFN)alpha enhanced the ability of the synthetic double-stranded RNA polyriboinosinic acid: polyribocytidilic acid (pI:C), but not interleukin-1 beta, to activate both p38 mitogen-activated kinase (MAPK) and extracellular signal-regulated kinase (ERK) signaling cascades. Activation by pI:C in IFN alpha-primed cells was delayed compared to activation with interleukin-1 beta, and this delay was followed by high, sustained activation of p38 MAPK and a modest elevation of ERK activation. Pharmacologic inhibition of either the ERK or the p38 MAPK pathway, using U0126 and SB203580, respectively, reduced interleukin-6 protein induction by at least 70%, and combined inhibition of both pathways fully blocked interleukin-6 protein expression and reduced interleukin-6 mRNA induction by more than 80%. In contrast, induction of double-stranded RNA-activated protein kinase (PKR) mRNA and protein by IFN alpha and/or pI:C was minimally affected by either inhibitor. Induction of interferon-regulatory factor-1 (IRF-1) by pI:C in IFN alpha primed cells was profoundly inhibited by U0126 but not by SB203580. Thus, IFN alpha priming enhances activation of p38 MAPK and ERK pathways by pI:C but not by interleukin-1 beta, thereby enhancing the expression of some, but not all, genes that are induced by pI:C.
Program in Biochemistry, Cellular and Developmental Biology, Emory University, Atlanta, Georgia, USA.
J L
JL
Harcourt
M K
MK
Offermann
D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000276:immunology*; D007375:Interleukin-1 / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D011119:Polynucleotides / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D002070:Butadienes; D004268:DNA-Binding Proteins; D007093:Imidazoles; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D007375:Interleukin-1; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D010750:Phosphoproteins; D011119:Polynucleotides; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C494257:IRF1 protein, human; C113580:U 0126; C093642:SB 203580