Tissue-specific autoregulation of the stat3 gene and its role in interleukin-6-induced survival signals in T cells.
Signal transducer and activator of transcription 3 (STAT3) mediates signals of various growth factors and cytokines, including interleukin-6 (IL-6). In certain IL-6-responsive cell lines, the stat3 gene is autoregulated by STAT3 through a composite IL-6 response element in its promoter that contains a STAT3-binding element (SBE) and a cyclic AMP-responsive element. To reveal the nature and roles of the stat3 autoregulation in vivo, we generated mice that harbor a mutation in the SBE (stat3(mSBE)). The intact SBE was crucial for IL-6-induced stat3 gene activation in the spleen, especially in the red pulp region, the kidney, and both mature and immature T lymphocytes. The SBE was not required, however, for IL-6-induced stat3 gene activation in hepatocytes. T lymphocytes from the stat3(mSBE/mSBE) mice were more susceptible to apoptosis despite the presence of IL-6 than those from wild-type mice. Consistent with this, IL-6-dependent activation of the Pim-1 and junB genes, direct target genes for STAT3, was attenuated in T lymphocytes of the stat3(mSBE/mSBE) mice. Thus, the tissue-specific autoregulation of the stat3 gene operates in vivo and plays a role in IL-6-induced antiapoptotic signaling in T cells.
Narimatsu
M
M
Department of Molecular Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Maeda
H
H
Itoh
S
S
Atsumi
T
T
Ohtani
T
T
Nishida
K
K
Itoh
M
M
Kamimura
D
D
Park
S J
SJ
Mizuno
K
K
Miyazaki
J
J
Hibi
M
M
Ishihara
K
K
Nakajima
K
K
Hirano
T
T
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D018390:Gene Targeting; D015850:Interleukin-6 / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D009154:Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D001616:beta-Galactosidase