Phosphatidylinositol 3-kinase regulates macrophage responses to double-stranded RNA and encephalomyocarditis virus.
Virus infection of macrophages stimulates the expression of proinflammatory and antiviral genes interleukin-1 (IL-1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In this study, we show that phosphatidylinositol 3-kinase (PI3K) is required for the inflammatory response of macrophages to virus infection. When macrophages are infected with encephalomyocarditis virus (EMCV) there is a rapid and transient activation of PI3K and phosphorylation of its downstream target Akt. Inhibitors of PI3K attenuate EMCV- and double-stranded RNA-induced iNOS, COX-2 and IL-1 beta expression in RAW264.7 cells and mouse peritoneal macrophages. The attenuation of inflammatory gene expression in response to PI3K inhibition correlates with the induction of macrophage apoptosis. The morphology of macrophages shifts from activation in response to EMCV infection to apoptosis in the cells treated with PI3K inhibitors and EMCV. These morphological changes are accompanied by the activation of caspase-3. These findings suggest that PI3K plays a central role in the regulation of macrophage responses to EMCV infection. When PI3K is activated, it participates in the regulation of inflammatory gene expression; however, if PI3K is inhibited macrophages are unable to mount an inflammatory antiviral response and die by apoptosis.
Freudenburg
Wieke
W
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
Moran
Jason M
JM
Lents
Nathan H
NH
Baldassare
Joseph J
JJ
Buller
R Mark L
RM
Corbett
John A
JA
D000818:Animals; D018188:Cardiovirus Infections / Q000201:enzymology / Q000276:immunology*; D053148:Caspase 3 / Q000276:immunology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000276:immunology; D004686:Encephalomyocarditis virus / Q000201:enzymology / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology*
D053583:Interleukin-1beta; D012330:RNA, Double-Stranded; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C505409:Casp3 protein, mouse; D053148:Caspase 3