PMID- 22331441
OWN - NLM
STAT- MEDLINE
DCOM- 20120803
LR  - 20120327
IS  - 1460-2377 (Electronic)
IS  - 0953-8178 (Linking)
VI  - 24
IP  - 4
DP  - 2012 Apr
TI  - Smad2 and Smad3 are redundantly essential for the suppression of iNOS synthesis 
      in macrophages by regulating IRF3 and STAT1 pathways.
PG  - 253-65
LID - 10.1093/intimm/dxr126 [doi]
AB  - Although transforming growth factor (TGF)-beta1 is a well-known immunosuppressive 
      cytokine, little is known about the role of its downstream transcription factors, 
      Smad2 and Smad3, in the suppression of macrophage activation. Previous studies 
      have demonstrated that Smad3 is critical for the suppression of LPS-mediated 
      inducible nitric oxide (NO) synthase (iNOS) induction, although the role of Smad2 
      remains to be investigated. In this study, we found that iNOS induction was 
      enhanced in Smad2-deficient bone marrow-derived macrophages (BMDMs) and 
      peritoneal macrophages in vitro and tumor-associated macrophages in vivo, 
      compared with wild-type (WT) macrophages. However, TGF-beta1 still suppressed iNOS 
      induction in Smad2-deficient macrophages. In Smad2/3 double knockout (KO) 
      (Smad2/3 DKO) BMDMs, LPS-mediated NO/iNOS induction was more strongly elevated 
      than in Smad2 or Smad3 single KO BMDMs, and its suppression by exogenous TGF-beta1 
      was severely impaired. These data suggest that Smad2 and Smad3 redundantly 
      regulate iNOS induction. Similarly, the production of IL-6 and TNFalpha, but not 
      IL-10 was augmented in Smad2/3 DKO BMDMs, suggesting that Smad2 and Smad3 also 
      redundantly suppressed some cytokines production. In Smad2/3 DKO macrophages, 
      TLR3- as well as TLR4-mediated IRF3 activation and IFN-beta production were strongly 
      augmented, which resulted in hyper STAT1 phosphorylation. Furthermore, IFN-beta- and 
      IFN-gamma-induced iNOS induction in the absence of TLR signaling and STAT1 
      transcriptional activity were augmented in Smad2/3 DKO BMDMs. These results 
      suggest that Smad2 and Smad3 negatively regulate iNOS induction in macrophages by 
      suppressing multiple steps in the IRF3-IFN-beta-STAT1 pathway.
FAU - Sugiyama, Yuki
AU  - Sugiyama Y
AD  - Department of Microbiology and Immunology, Keio University School of Medicine, 
      Shinjuku-ku, Tokyo 160-8582, Japan.
FAU - Kakoi, Kyosuke
AU  - Kakoi K
FAU - Kimura, Akihiro
AU  - Kimura A
FAU - Takada, Ichiro
AU  - Takada I
FAU - Kashiwagi, Ikko
AU  - Kashiwagi I
FAU - Wakabayashi, Yu
AU  - Wakabayashi Y
FAU - Morita, Rimpei
AU  - Morita R
FAU - Nomura, Masatoshi
AU  - Nomura M
FAU - Yoshimura, Akihiko
AU  - Yoshimura A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120213
PL  - England
TA  - Int Immunol
JT  - International immunology
JID - 8916182
RN  - 0 (Interferon Regulatory Factor-3)
RN  - 0 (Interleukin-6)
RN  - 0 (Irf3 protein, mouse)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (Smad2 Protein)
RN  - 0 (Smad2 protein, mouse)
RN  - 0 (Smad3 Protein)
RN  - 0 (Smad3 protein, mouse)
RN  - 0 (Stat1 protein, mouse)
RN  - 0 (TLR3 protein, mouse)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 3)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 130068-27-8 (Interleukin-10)
RN  - 77238-31-4 (Interferon-beta)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/immunology
MH  - Cells, Cultured
MH  - Interferon Regulatory Factor-3/metabolism
MH  - Interferon-beta/biosynthesis/metabolism
MH  - Interferon-gamma/metabolism
MH  - Interleukin-10
MH  - Interleukin-6/biosynthesis
MH  - Macrophage Activation
MH  - Macrophages/immunology/*metabolism
MH  - Macrophages, Peritoneal/immunology/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Nitric Oxide Synthase Type II/*biosynthesis
MH  - STAT1 Transcription Factor/metabolism
MH  - Signal Transduction
MH  - Smad2 Protein/deficiency/genetics/*metabolism
MH  - Smad3 Protein/deficiency/genetics/*metabolism
MH  - Toll-Like Receptor 3/immunology
MH  - Toll-Like Receptor 4/immunology
MH  - Transcription, Genetic
MH  - Transforming Growth Factor beta1/immunology/metabolism
EDAT- 2012/02/15 06:00
MHDA- 2012/08/04 06:00
CRDT- 2012/02/15 06:00
PHST- 2012/02/15 06:00 [entrez]
PHST- 2012/02/15 06:00 [pubmed]
PHST- 2012/08/04 06:00 [medline]
AID - dxr126 [pii]
AID - 10.1093/intimm/dxr126 [doi]
PST - ppublish
SO  - Int Immunol. 2012 Apr;24(4):253-65. doi: 10.1093/intimm/dxr126. Epub 2012 Feb 13.