Research ArticleImmunology

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

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Science Signaling  16 Jun 2009:
Vol. 2, Issue 75, pp. ra28
DOI: 10.1126/scisignal.2000202

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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–α (TNF-α). A modulator of this proinflammatory response is prostaglandin E2 (PGE2), which activates G protein–coupled receptors that couple to Gαs, leading to the production of cyclic adenosine monophosphate (cAMP). As well as inhibiting the production of TNF-α 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-α expression involved phosphorylation of the NF-κB 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.