Akt/protein kinase B modulates macrophage inflammatory response to Francisella infection and confers a survival advantage in mice

被引:97
作者
Rajaram, Murugesan V. S.
Ganesan, Latha P.
Parsa, Kishore V. L.
Butchar, Jonathan P.
Gunn, John S.
Tridandapani, Susheela
机构
[1] Ohio State Univ, Dorothy M Davis Heart & Lung Res Inst, Columbus, OH 43210 USA
[2] Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA
[3] Ohio State Univ, Dept Mol Virol, Columbus, OH 43210 USA
[4] Ohio State Univ, Ctr Microbial Interface Biol, Columbus, OH 43210 USA
关键词
D O I
10.4049/jimmunol.177.9.6317
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The Gram-negative bacterium Francisella novicida infects primarily monocytes/macrophages and is highly virulent in mice. Macrophages respond by producing inflammatory cytokines that confer immunity against the infection. However, the molecular details of host cell response to Francisella infection are poorly understood. In this study, we demonstrate that F. novicida infection of murine macrophages induces the activation of Akt. Inhibition of Akt significantly decreases proinflammatory cytokine production in infected macrophages, whereas production of the anti -inflammatory cytokine IL-10 is enhanced. Analysis of the mechanism of Akt influence on cytokine response demonstrated that Akt promotes NF-kappa B activation. We have extended these findings to show that Akt activation may be regulated by bacterial genes associated with phagosomal escape. Infection with mglA mutants of F. novicida elicited sustained activation of Akt in comparison to cells infected with wild-type F. novicida. Concomitantly, there was significantly higher proinflammatory cytokine production and lower IL-10 production in cells infected with the mglA mutant. Finally, transgenic animals expressing constitutively active Akt displayed a survival advantage over their wild-type littermates when challenged with lethal doses of F. novicida. Together, these observations indicate that Akt promotes proinflammatory cytokine production by F. novicida-infected macrophages through its influence on NF-kappa B, thereby contributing to immunity against F. novicida infection.
引用
收藏
页码:6317 / 6324
页数:8
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