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


Editor's Summary

Specific Scaffolds
Macrophages are innate immune cells that mediate early responses to infection by sensing microbial products through Toll-like receptors (TLRs) and producing proinflammatory compounds, such as tumor necrosis factor–{alpha} (TNF-{alpha}). A modulator of this proinflammatory response is prostaglandin E2 (PGE2), which activates G protein–coupled receptors that couple to G{alpha}s, leading to the production of cyclic adenosine monophosphate (cAMP). As well as inhibiting the production of TNF-{alpha} by macrophages in response to the TLR4 agonist LPS, PGE2 and cAMP also stimulate the production of the anti-inflammatory cytokines interleukin-10 (IL-10) and granulocyte colony-stimulating factor (G-CSF) (see the Perspective by Peters-Golden). Wall et al. found that the pleiotropic effects of PGE2 and cAMP on LPS-stimulated cytokine production depended on the fate of cAMP-dependent protein kinase (PKA). Selective binding of activated PKA to different scaffold proteins known as A kinase–anchoring proteins (AKAPs) resulted in differential effects on the expression of genes encoding cytokines. In particular, cAMP-dependent inhibition of TNF-{alpha} expression involved phosphorylation of the NF-{kappa}B transcription factor p105 by PKA bound to AKAP95, which inhibited the nuclear translocation of the transcription factor, whereas the effect of PKA on the enhancement of G-CSF expression was mediated by another AKAP; the effect of PKA on IL-10 expression was AKAP-independent. Together, these data uncover crosstalk between TLR4 and cAMP signaling pathways that depend on the differential localization of PKA by different scaffold proteins, which could have implications for anti-inflammatory therapies.

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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