Suppression of LPS-induced TNF-α production in macrophages by cAMP Is mediated by PKA-AKAP95-p105

Estelle A. Wall, Joelle R. Zavzavadjian, Chang Sook Mi, Baljinder Randhawa, Xiaocui Zhu, Robert C. Hsueh, Jamie Liu, Adrienne Driver, Xiaoyan Robert Bao, Paul C. Sternweis, Melvin I. Simon, Iain D C Fraser

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125 Scopus citations

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 E2, 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, timelapse 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-α, which involved phosphorylation of p105 (also known as Nfkb1) by PKA at a site adjacent to the region targeted by inhibitor of nuclear factor κB 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.

Original languageEnglish (US)
JournalScience Signaling
Volume2
Issue number75
DOIs
StatePublished - Jun 16 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Wall, E. A., Zavzavadjian, J. R., Mi, C. S., Randhawa, B., Zhu, X., Hsueh, R. C., Liu, J., Driver, A., Bao, X. R., Sternweis, P. C., Simon, M. I., & Fraser, I. D. C. (2009). Suppression of LPS-induced TNF-α production in macrophages by cAMP Is mediated by PKA-AKAP95-p105. Science Signaling, 2(75). https://doi.org/10.1126/scisignal.2000202