Faculty Collaboration Database

Novel role for calcium-independent phospholipase A(2) in the macrophage antiviral response of inducible nitric-oxide synthase expression. J Biol Chem 2002 Oct 11;277(41):38449-55

Date

08/09/2002

Pubmed ID

12167650

DOI

10.1074/jbc.M206247200

Scopus ID

2-s2.0-0037064090 (requires institutional sign-in at Scopus site)   40 Citations

Abstract

The double-stranded (ds) RNA-dependent protein kinase (PKR) is a primary regulator of antiviral responses; however, the ability of dsRNA to activate nuclear factor-kappa B (NF-kappa B) and dsRNA + interferon gamma (IFN-gamma) to stimulate inducible nitric-oxide synthase (iNOS) expression by macrophages isolated from PKR(-/-) mice suggests that signaling pathways in addition to PKR participate in antiviral activities. We have identified a novel phospholipid-signaling cascade that mediates macrophage activation by dsRNA and viral infection. Bromoenol lactone (BEL), a selective inhibitor of the calcium-independent phospholipase A(2) (iPLA(2)), prevents dsRNA- and virus-induced iNOS expression by RAW 264.7 cells and mouse macrophages. BEL does not modulate dsRNA-induced interleukin 1 expression, nor does it affect dsRNA-induced NF-kappa B activation. Protein kinase A (PKA) and the cAMP response element binding protein (CREB) are downstream targets of iPLA(2), because selective PKA inhibition prevents dsRNA-induced iNOS expression, and the inhibitory actions of BEL on dsRNA-induced iNOS expression are overcome by the direct activation of PKA. In addition, BEL inhibits dsRNA-induced CREB phosphorylation and CRE reporter activation. PKR does not participate in iPLA(2) activation or iNOS expression, because dsRNA stimulates iPLA(2) activity and dsRNA + IFN-gamma induces iNOS expression and nitric oxide production to similar levels by macrophages isolated from PKR(+/+) and PKR(-/-) mice. These findings support a PKR-independent signaling role for iPLA(2) in the antiviral response of macrophages.

Author List

Maggi LB Jr, Moran JM, Scarim AL, Ford DA, Yoon JW, McHowat J, Buller RM, Corbett JA

Author

John A. Corbett PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Cell Line
Cyclic AMP Response Element-Binding Protein
Cyclic AMP-Dependent Protein Kinase Type II
Cyclic AMP-Dependent Protein Kinases
Encephalomyocarditis virus
Enzyme Activation
Genes, Reporter
Humans
Interferon-gamma
Interleukin-1
Macrophage Activation
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B
Naphthalenes
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Phosphodiesterase Inhibitors
Phospholipases A
Phospholipids
Pyrones
RNA, Double-Stranded
Signal Transduction
eIF-2 Kinase