Suppression of LPS-Induced TNF-α Production in Macrophages by cAMP Is Mediated by PKA-AKAP95-p105

被引：158

作者：

Wall, Estelle A. ^{[1
]}

Zavzavadjian, Joelle R. ^{[1
]}

Chang, Mi Sook ^{[1
]}

Randhawa, Baljinder ^{[1
]}

Zhu, Xiaocui ^{[1
]}

Hsueh, Robert C. ^{[2
]}

Liu, Jamie ^{[1
]}

Driver, Adrienne ^{[1
]}

Bao, Xiaoyan Robert ^{[1
]}

Sternweis, Paul C. ^{[2
]}

Simon, Melvin I. ^{[1
]}

Fraser, Iain D. C. ^{[1
]}

机构：

[1] CALTECH, Div Biol, Pasadena, CA 91125 USA

[2] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

来源：

SCIENCE SIGNALING | 2009年 / 2卷 / 75期

关键词：

NF-KAPPA-B; PROTEIN-KINASE-A; NECROSIS-FACTOR-ALPHA; VASOACTIVE-INTESTINAL-PEPTIDE; CYCLIC-AMP; ANCHORING PROTEIN; RNA INTERFERENCE; INNATE IMMUNITY; SIGNALING COMPLEXES; MONOCYTIC CELLS;

D O I：

10.1126/scisignal.2000202

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The activation of macrophages through Toll-like receptor (TLR) pathways leads to the production of a broad array of cytokines and mediators that coordinate the immune response. The inflammatory potential of this response can be reduced by compounds, such as prostaglandin E-2, that induce the production of cyclic adenosine monophosphate (cAMP). Through experiments with cAMP analogs and multigene RNA interference (RNAi), we showed that key anti-inflammatory effects of cAMP were mediated specifically by cAMP-dependent protein kinase (PKA). Selective inhibitors of PKA anchoring, time-lapse microscopy, and RNAi screening suggested that differential mechanisms of PKA action existed. We showed a specific role for A kinase-anchoring protein 95 in suppressing the expression of the gene encoding tumor necrosis factor-alpha, which involved phosphorylation of p105 (also known as Nfkb1) by PKA at a site adjacent to the region targeted by inhibitor of nuclear factor kappa B kinases. These data suggest that crosstalk between the TLR4 and cAMP pathways in macrophages can be coordinated through PKA-dependent scaffolds that localize specific pools of the kinase to distinct substrates.

引用

页数：16

共 76 条

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