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Sci. Signal., 16 June 2009
Vol. 2, Issue 75, p. ra28
[DOI: 10.1126/scisignal.2000202]

RESEARCH ARTICLES

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

Estelle A. Wall1*{dagger}, Joelle R. Zavzavadjian1*{ddagger}, Mi Sook Chang1*§, Baljinder Randhawa1||, Xiaocui Zhu1, Robert C. Hsueh2#, Jamie Liu1, Adrienne Driver1**, Xiaoyan Robert Bao1{dagger}{dagger}, Paul C. Sternweis2, Melvin I. Simon1{dagger}, and Iain D. C. Fraser1{ddagger}{ddagger}§§

1 Alliance for Cellular Signaling, Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
2 Alliance for Cellular Signaling, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

* These authors contributed equally to this work

{dagger} Present address: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.

{ddagger} Present address: TMT Observatory Corporation, Pasadena, CA 91125, USA.

§ Present address: Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA.

|| Present address: Xencor, Monrovia, CA 91016, USA.

Present address: Astellas Research Institute of America, Skokie, IL 60077, USA.

# Present address: Cadent Medical Communications, Irving, TX 75063, USA.

** Present address: Truman College, Chicago, IL 60640, USA.

{dagger}{dagger} Present address: Massachusetts General Hospital, Boston, MA 02114, USA.

{ddagger}{ddagger} Present address: Program in Systems Immunology and Infectious Disease Modeling, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 33, Rm. 3W20B.4, 33 North Drive, MSC-8180, Bethesda, MD 20892, USA.

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, 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.

§§ To whom correspondence should be addressed. E-mail: fraseri{at}niaid.nih.gov

Citation: E. A. Wall, J. R. Zavzavadjian, M. S. Chang, B. Randhawa, X. Zhu, R. C. Hsueh, J. Liu, A. Driver, X. R. Bao, P. C. Sternweis, M. I. Simon, I. D. C. Fraser, Suppression of LPS-Induced TNF-{alpha} Production in Macrophages by cAMP Is Mediated by PKA-AKAP95-p105. Sci. Signal. 2, ra28 (2009).

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