Suppression of LPS-Induced TNF-α Production in Macrophages by cAMP Is Mediated by PKA-AKAP95-p105
| Autor: | Xiaocui Zhu, Jamie Liu, Baljinder Randhawa, Mi Sook Chang, Robert C. Hsueh, Melvin I. Simon, Paul C. Sternweis, Xiaoyan Robert Bao, Estelle A. Wall, Iain D. C. Fraser, Adrienne Driver, Joelle R. Zavzavadjian |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Lipopolysaccharides
A Kinase Anchor Proteins Biology Biochemistry Second Messenger Systems Article Dinoprostone Cell Line chemistry.chemical_compound Mice RNA interference Cyclic AMP Animals Cyclic adenosine monophosphate Phosphorylation Protein kinase A Molecular Biology Inflammation Kinase Tumor Necrosis Factor-alpha Macrophages NF-kappa B p50 Subunit Cell Biology NFKB1 Molecular biology Cyclic AMP-Dependent Protein Kinases Toll-Like Receptor 4 chemistry Gene Expression Regulation TLR4 biology.protein Tumor necrosis factor alpha RNA Interference CREB1 |
| Popis: | 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 kappaB 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|