Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo.
Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKKβ-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-α, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses.
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan.
Ryoko
R
Yoshida
Mayu
M
Suzuki
Ryota
R
Sakaguchi
Eiichi
E
Hasegawa
Akihiro
A
Kimura
Takashi
T
Shichita
Takashi
T
Sekiya
Hiroshi
H
Shiraishi
Kouji
K
Shimoda
Akihiko
A
Yoshimura
D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology*; D000818:Animals; D039521:CD11c Antigen / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
D039521:CD11c Antigen; D016207:Cytokines; D016760:Proto-Oncogene Proteins c-fos