TY - JOUR
T1 - Novel role for calcium-independent phospholipase A2 in the macrophage antiviral response of inducible nitric-oxide synthase expression
AU - Maggi, Leonard B.
AU - Moran, Jason M.
AU - Scarim, Anna L.
AU - Ford, David A.
AU - Yoon, Ji Won
AU - McHowat, Jane
AU - Buller, R. Mark L.
AU - Corbett, John A.
PY - 2002/10/11
Y1 - 2002/10/11
N2 - 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-κB (NF-κB) and dsRNA + interferon γ (IFN-γ) 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 A2 (iPLA2), 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-κB activation. Protein kinase A (PKA) and the cAMP response element binding protein (CREB) are downstream targets of iPLA2, 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 iPLA2 activation or iNOS expression, because dsRNA stimulates iPLA2 activity and dsRNA + IFN-γ 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 iPLA2 in the antiviral response of macrophages.
AB - 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-κB (NF-κB) and dsRNA + interferon γ (IFN-γ) 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 A2 (iPLA2), 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-κB activation. Protein kinase A (PKA) and the cAMP response element binding protein (CREB) are downstream targets of iPLA2, 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 iPLA2 activation or iNOS expression, because dsRNA stimulates iPLA2 activity and dsRNA + IFN-γ 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 iPLA2 in the antiviral response of macrophages.
UR - http://www.scopus.com/inward/record.url?scp=0037064090&partnerID=8YFLogxK
U2 - 10.1074/jbc.M206247200
DO - 10.1074/jbc.M206247200
M3 - Article
C2 - 12167650
AN - SCOPUS:0037064090
VL - 277
SP - 38449
EP - 38455
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 41
ER -