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

Keiko Koga, Giichi Takaesu, Ryoko Yoshida, Mako Nakaya, Takashi Kobayashi, Ichiko Kinjyo, Akihiko Yoshimura

Research output: Contribution to journalArticle

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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-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.

Original languageEnglish
Pages (from-to)372-383
Number of pages12
JournalImmunity
Volume30
Issue number3
DOIs
Publication statusPublished - 2009 Mar 20

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Proto-Oncogene Proteins c-fos
Cyclic AMP
Cytokines
Interleukin-12
Interleukin-10
Dendritic Cells
Lipopolysaccharides
Immunosuppressive Agents
Innate Immunity
Small Interfering RNA
Proteins
Transcription Factors

Keywords

  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein. / Koga, Keiko; Takaesu, Giichi; Yoshida, Ryoko; Nakaya, Mako; Kobayashi, Takashi; Kinjyo, Ichiko; Yoshimura, Akihiko.

In: Immunity, Vol. 30, No. 3, 20.03.2009, p. 372-383.

Research output: Contribution to journalArticle

Koga, Keiko ; Takaesu, Giichi ; Yoshida, Ryoko ; Nakaya, Mako ; Kobayashi, Takashi ; Kinjyo, Ichiko ; Yoshimura, Akihiko. / Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein. In: Immunity. 2009 ; Vol. 30, No. 3. pp. 372-383.
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