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Published June 16, 2009 | public
Journal Article

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


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

Additional Information

© 2009 American Association for the Advancement of Science. Submitted 15 December 2008; accepted 29 May 2009; final Publication 16 June 2009. This work was supported by National Institute of General Medical Sciences Grant U54 GM062114. We thank L. Cheadle for excellent technical assistance and Alliance for Cellular Signaling colleagues for insight and advice. We are grateful to M. Covert and D. Baltimore for provision of the GFP-p65 construct, V. Coghlan for AKAP95 antisera, and W. Frankel and Y. Yang for the AKAP95GT mice.

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