Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the phosphorylated c-Fos protein.
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.
Koga
Keiko
K
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Takaesu
Giichi
G
Yoshida
Ryoko
R
Nakaya
Mako
M
Kobayashi
Takashi
T
Kinjyo
Ichiko
I
Yoshimura
Akihiko
A
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000145:classification / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D016760:Proto-Oncogene Proteins c-fos; D000242:Cyclic AMP; D051550:I-kappa B Kinase