title: ERK activation is required for double-stranded RNA- and virus-induced interleukin-1 expression by macrophages.
abstract: Double-stranded (ds) RNA, which accumulates during viral replication, activates the antiviral response of infected cells. In this study, we have identified a requirement for extracellular signal-regulated kinase (ERK) in the regulation of interleukin 1 (IL-1) expression by macrophages in response to dsRNA and viral infection. Treatment of RAW 264.7 cells or mouse macrophages with dsRNA stimulates ERK phosphorylation that is first apparent following a 15-min incubation and persists for up to 60 min, the accumulation of iNOS and IL-1 mRNA following a 6-h incubation, and the expression of iNOS and IL-1 at the protein level following a 24-h incubation. Inhibitors of ERK activation prevent dsRNA-induced ERK phosphorylation and IL-1 expression by macrophages. The regulation of macrophage activation by ERK appears to be selective for IL-1, as ERK inhibition does not attenuate dsRNA-induced iNOS expression by macrophages. dsRNA stimulates both ERK activation and IL-1 expression by macrophages isolated from dsRNA-dependent protein kinase (PKR)-deficient mice, indicating that PKR does not participate in this antiviral response. These findings support a novel PKR-independent role for ERK in the regulation of the antiviral response of IL-1 expression and release by macrophages.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Maggi
authors.forename: Jason M
authors.initials: JM
authors.lastname: Moran
authors.forename: R Mark L
authors.initials: RM
authors.lastname: Buller
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000378:metabolism*; D002478:Cells, Cultured; D004686:Encephalomyocarditis virus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000821:virology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D012330:RNA, Double-Stranded / Q000378:metabolism* / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D007375:Interleukin-1; D012330:RNA, Double-Stranded; D019892:eIF-2 Kinase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one