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- Title
Phosphatidylinositol 3-Kinase Regulates the Inflammatory Response of Macrophages to dsRNA and Encephalomyocarditis Virus.
- Authors
de Graaf, Wieke; Moran, Jason M.; Buller, R. Mark L.; Corbett, John A.
- Abstract
Type I diabetes mellitus is an autoimmune disease characterized by selective destruction of insulin secreting pancreatic β-cells. Virus infection has been proposed as an environmental factor that may initiate autoimmune-mediated β-cell damage. An animal model of encephalomyocarditis virus (EMCV)-induced diabetes suggests that activation of macrophages is essential for the development of diabetes in response to virus infection. Infection of macrophages with EMCV or dsRNA induces expression of inflammatory genes, including inducible nitric oxide synthase (iNOS) and interleukin-1 β (IL-1 β), which mediate β-cell damage. The mechanisms of macrophage activation in response to virus infection axe incompletely understood. Phosphatidylinositol 3-kinase (PI3K) is activated in response to several viruses. In this study, the role of PI3K in the regulation of macrophage inflammatory gene expression (IL-1 β, iNOS and cyclooxygenase-2 (COX-2)) following virus infection was examined. Infection of RAW264.7 cells with EMCV results in the rapid and transient activation of PI3K activity and the phosphorylation of Akt, a downstream target of PI3K. Inhibition of PI3K results in attenuation of EMCV- or dsRNA-induced iNOS expression and nitric oxide production as well as COX-2 and IL-1 β expression. While dsRNA-induced IL-1 β and COX-2 expression are regulated by MAPK signalling, specifically ERK for IL-1 and JNK and p38 for COX-2, PI3K inhibition did not attenuate ERK, p38 and JNK phosphorylation following dsRNA treatment. The mechanism by which EMCV and dsRNA activate PI3K appears to require Src activation. Inhibition of Src protein tyrosine kinase activity attenuates EMCV- or dsRNA-induced Akt phosphorylation and iNOS expression in RAW264.7 cells, suggesting that Src regulates PI3K activation in response to virus infection. Our findings support a role for PI3K in the inflammatory response of macrophages to virus infection.
- Publication
Diabetes, 2007, Vol 56, pA325
- ISSN
0012-1797
- Publication type
Academic Journal