Open AccessMultiple signaling cascades are differentially involved in gene induction by double stranded RNA in interferon‐α‐primed cells
Author(s) -
Harcourt Jennifer L.,
Offermann Margaret K.
Publication year - 2001
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2001.02003.x
Subject(s) - mapk/erk pathway , signal transduction , p38 mitogen activated protein kinases , kinase , protein kinase a , microbiology and biotechnology , biology , interferon , mitogen activated protein kinase , priming (agriculture) , chemistry , immunology , botany , germination
Priming with interfon (IFN)α enhanced the ability of the synthetic double‐stranded RNA polyriboinosinic acid: polyribocytidilic acid (pI:C), but not interleukin‐1β, to activate both p38 mitogen‐activated kinase (MAPK) and extracellular signal‐regulated kinase (ERK) signaling cascades. Activation by pI:C in IFNα‐primed cells was delayed compared to activation with interleukin‐1β, 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 IFNα and/or pI:C was minimally affected by either inhibitor. Induction of interferon‐regulatory factor‐1 (IRF‐1) by pI:C in IFNα primed cells was profoundly inhibited by U0126 but not by SB203580. Thus, IFNα priming enhances activation of p38 MAPK and ERK pathways by pI:C but not by interleukin‐1β, thereby enhancing the expression of some, but not all, genes that are induced by pI:C.