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Molecular and Cellular Biology, October 2001, p. 6615-6625, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6615-6625.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Tissue-Specific Autoregulation of the stat3 Gene and Its Role in Interleukin-6-Induced Survival Signals in T Cells

Masahiro Narimatsu,1,dagger Hisoka Maeda,1 Shousaku Itoh,1 Toru Atsumi,1 Takuya Ohtani,2 Keigo Nishida,1 Motoyuki Itoh,1,Dagger Daisuke Kamimura,1 Sung-Joo Park,1 Katsunori Mizuno,1 Jun-ichi Miyazaki,3 Masahiko Hibi,1 Katsuhiko Ishihara,1 Koichi Nakajima,2 and Toshio Hirano1,*

Department of Molecular Oncology1 and Department of Nutrition and Physiological Chemistry,3 Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, and Department of Immunology, Osaka City University Graduate School of Medicine, Osaka 545-8485,2 Japan

Received 7 March 2001/Returned for modification 21 May 2001/Accepted 2 July 2001

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 (stat3mSBE). 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 stat3mSBE/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 stat3mSBE/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.

* Corresponding author. Mailing address: Department of Molecular Oncology (C7), Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3880. Fax: 81-6-6879-3889. E-mail: hirano{at}molonc.med.osaka-u.ac.jp.

dagger Present address: Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.

Dagger Present address: Unit on Vertebrate Neural Development, Laboratory of Molecular Genetics, NICHD/NIH, Bethesda, MD 20892.

Molecular and Cellular Biology, October 2001, p. 6615-6625, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6615-6625.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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