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Title: Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo

Abstract

Highlights: Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos produced less inflammatory cytokines. Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos activated T cells less efficiently. Black-Right-Pointing-Pointer Transgenic mice expressing stabilized c-Fos were resistant to EAE model. -- Abstract: 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 IKK{beta}-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-{alpha}, 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 amore » suppressive role in certain innate and adaptive immune responses.« less

Authors:
; ; ; ; ; ;  [1];  [2];  [3];  [4];  [1];  [2]
  1. Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582 (Japan)
  2. (Japan)
  3. Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga (Japan)
  4. Department of Laboratory Animal Center, Keio University School of Medicine, Tokyo (Japan)
Publication Date:
OSTI Identifier:
22207912
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 423; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMP; BONE MARROW; CELL PROLIFERATION; DENDRITES; HALF-LIFE; IMMUNITY; IN VIVO; INFLAMMATION; INHIBITION; LYMPHOKINES; MUTATIONS; PHOSPHORYLATION; TRANSCRIPTION FACTORS; TRANSGENIC MICE

Citation Formats

Yoshida, Ryoko, Suzuki, Mayu, Sakaguchi, Ryota, Hasegawa, Eiichi, Kimura, Akihiro, Shichita, Takashi, Sekiya, Takashi, Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075, Shiraishi, Hiroshi, Shimoda, Kouji, Yoshimura, Akihiko, E-mail: yoshimura@a6.keio.jp, and Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075. Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.05.097.
Yoshida, Ryoko, Suzuki, Mayu, Sakaguchi, Ryota, Hasegawa, Eiichi, Kimura, Akihiro, Shichita, Takashi, Sekiya, Takashi, Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075, Shiraishi, Hiroshi, Shimoda, Kouji, Yoshimura, Akihiko, E-mail: yoshimura@a6.keio.jp, & Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075. Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo. United States. doi:10.1016/J.BBRC.2012.05.097.
Yoshida, Ryoko, Suzuki, Mayu, Sakaguchi, Ryota, Hasegawa, Eiichi, Kimura, Akihiro, Shichita, Takashi, Sekiya, Takashi, Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075, Shiraishi, Hiroshi, Shimoda, Kouji, Yoshimura, Akihiko, E-mail: yoshimura@a6.keio.jp, and Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075. Fri . "Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo". United States. doi:10.1016/J.BBRC.2012.05.097.
@article{osti_22207912,
title = {Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo},
author = {Yoshida, Ryoko and Suzuki, Mayu and Sakaguchi, Ryota and Hasegawa, Eiichi and Kimura, Akihiro and Shichita, Takashi and Sekiya, Takashi and Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075 and Shiraishi, Hiroshi and Shimoda, Kouji and Yoshimura, Akihiko, E-mail: yoshimura@a6.keio.jp and Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075},
abstractNote = {Highlights: Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos produced less inflammatory cytokines. Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos activated T cells less efficiently. Black-Right-Pointing-Pointer Transgenic mice expressing stabilized c-Fos were resistant to EAE model. -- Abstract: 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 IKK{beta}-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-{alpha}, 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.},
doi = {10.1016/J.BBRC.2012.05.097},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 423,
place = {United States},
year = {2012},
month = {6}
}