Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein

Abstract

Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production from monocytic cells. Enhanced expression of interleukin-10 (IL-10) has been suggested to be the mechanism of suppression. However, cAMP is still capable of suppressing production of the cytokines TNF-alpha and IL-12 in IL-10-deficient dendritic cells (DCs). Here, we demonstrated that the transcription factor c-Fos was responsible for the cAMP-mediated suppression of inflammatory cytokine production. c-Fos accumulated at high amounts in response to cAMP and lipopolysaccharide (LPS). Overexpression of c-Fos suppressed LPS-induced cytokine production, whereas cAMP-mediated suppression of TNF-alpha and IL-12 was impaired in Fos(-/-) DCs or in RAW264.7 cells treated with c-Fos siRNA. c-Fos physically interacted with p65 protein and reduced the recruitment of p65 to the Tnf promoter. Multiple sites of c-Fos were phosphorylated by the IKKbeta protein. Thus, we propose that c-Fos is a substrate of IKKbeta and is responsible for the immunosuppressive effect of cAMP.

Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1

“…It has been reported that c-Fos inhibits the inflammatory response of myeloid-derived immune cells (22,23). In this study, we demonstrated that c-Fos (AP-1) also suppresses antitumor T-cell function.…”

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

“…That PGE2 can suppress LPS-induced inflammatory cytokine and type I IFN secretion is known, however the mechanism of these suppressive effects has been controversial (12,14). One study showed suppression of the NF-κB pathway by cAMP, a downstream effecter molecule of PGE2 signaling, whereas another argued that the NF-κB pathway is unaffected by cAMP signaling (15,16). We found no evidence that the NF-κB pathway is affected by PGE2 signaling (Fig.…”

“…The observations showing that dead cell-derived PGE2 inhibits the LPS-mediated induction of Tnf and Ifnb1 mRNA also prompted us to study the underlying mechanism, which has been poorly understood (12,(14)(15)(16). Because the induction of TNF-α by LPS requires activation of NF-κB and MAPK pathways (3, 4), we next examined the effect of PGE2 on the LPS-mediated activation of canonical NF-κB and MAPK in RAW 264.7 cells.…”

“…PGE2 is the main product of two cyclooxygenases, COX-1 and COX-2, of which COX-1 is constitutively expressed and COX-2 is induced by various stimuli such as cytokines and various PAMPs (12,13). PGE2 is the most abundant eicosanoid lipid in the inflammatory environment, and its receptors EP2 and EP4 and their downstream signaling to cAMP are proposed for the suppression of inflammation, although the precise mechanism is unclear (10,12,(14)(15)(16). COX-2 is also overexpressed in various forms of cancer, and PGE2 produced by COX-2 has been implicated in the exacerbation of cancer (11,13).…”

Histone 3 Lysine 9 (H3K9) Methyltransferase Recruitment to the Interleukin-2 (IL-2) Promoter Is a Mechanism of Suppression of IL-2 Transcription by the Transforming Growth Factor-β-Smad Pathway

“…Cellular debris was removed by centrifugation at 15,000 ϫ g for 5 min. Proteins from cell lysates were precipitated with 1 g of an antibody and 20 l of protein G-Sepharose (GE Healthcare) for 2 h at 4°C (23). The immune complex was washed three times with washing buffer containing 20 mM Hepes (pH 7.4), 500 mM NaCl, and 10 mM MgCl 2 and was suspended in 40 l of rinse buffer containing 20 mM Hepes (pH 7.4), 150 mM NaCl, and 10 mM MgCl 2 .…”