TY - JOUR
T1 - Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein
AU - Koga, Keiko
AU - Takaesu, Giichi
AU - Yoshida, Ryoko
AU - Nakaya, Mako
AU - Kobayashi, Takashi
AU - Kinjyo, Ichiko
AU - Yoshimura, Akihiko
N1 - Funding Information:
We thank K. Takeda (Osaka University) for providing Il10 −/− and STAT3-flox mice; S. Okada (Kumamoto University) for Fos −/− mice; Y. Nakabeppu (Kyushu University) for c-Fos, FosB, and Fra1 cDNAs; and T. Ishitani (Kyushu University) for GST-IκBα plasmid. We also thank T. Yoshioka, M. Ohtsu, K. Fukidome, and M. Asakawa for technical assistance and N. Soma and Y. Nishi for manuscript preparation. This study was supported by special Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO); Astellas Foundation for Research on Metabolic Disorders; the Japan Intractable Disease Research Foundation; the Mochida Memorial Foundation; the Naito Memorial Foundation; and the Princess Takamatsu Cancer Research Fund.
PY - 2009/3/20
Y1 - 2009/3/20
N2 - 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-α 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-α 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 IKKβ protein. Thus, we propose that c-Fos is a substrate of IKKβ and is responsible for the immunosuppressive effect of cAMP.
AB - 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-α 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-α 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 IKKβ protein. Thus, we propose that c-Fos is a substrate of IKKβ and is responsible for the immunosuppressive effect of cAMP.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=62049085056&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62049085056&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2008.12.021
DO - 10.1016/j.immuni.2008.12.021
M3 - Article
C2 - 19285436
AN - SCOPUS:62049085056
SN - 1074-7613
VL - 30
SP - 372
EP - 383
JO - Immunity
JF - Immunity
IS - 3
ER -
