title: Suppression of LPS-induced TNF-alpha production in macrophages by cAMP is mediated by PKA-AKAP95-p105.
abstract: 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.
authors.affiliation: Alliance for Cellular Signaling, Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Estelle A
authors.initials: EA
authors.lastname: Wall
authors.forename: Joelle R
authors.initials: JR
authors.lastname: Zavzavadjian
authors.forename: Mi Sook
authors.initials: MS
authors.lastname: Chang
authors.forename: Baljinder
authors.initials: B
authors.lastname: Randhawa
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Zhu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hsueh
authors.forename: Jamie
authors.initials: J
authors.lastname: Liu
authors.forename: Adrienne
authors.initials: A
authors.lastname: Driver
authors.forename: Xiaoyan Robert
authors.initials: XR
authors.lastname: Bao
authors.forename: Paul C
authors.initials: PC
authors.lastname: Sternweis
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Iain D C
authors.initials: ID
authors.lastname: Fraser
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D034622:RNA Interference; D015290:Second Messenger Systems / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
chemical_list: D054758:A Kinase Anchor Proteins; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C073701:Nfkb1 protein, mouse; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone