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J. Biol. Chem., Vol. 279, Issue 24, 25204-25210, June 11, 2004

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A Constitutively Active Arylhydrocarbon Receptor Induces Growth Inhibition of Jurkat T Cells through Changes in the Expression of Genes Related to Apoptosis and Cell Cycle Arrest^*

Tomohiro Ito, Shin-ichi Tsukumo, Norio Suzuki, Hozumi Motohashi, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama, Junsei Mimura, Tien-Min Lin¶, Richard E. Peterson¶, Chiharu Tohyama, and Keiko Nohara||

From the Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan, the Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8575, Japan, and the ^¶School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to suppress T cell-dependent immune reactions through the activation of the arylhydrocarbon receptor (AhR). Our previous findings suggest that TCDD inhibits the activation and subsequent expansion of T cells following antigen stimulation in mice, leading to a decreased level of T cell-derived cytokines involved in antibody production. In the present study, we investigated the effects of activated AhR on T cells by transiently expressing a constitutively active AhR (CA-AhR) mutant in AhR-null Jurkat T cells. In agreement with our previous findings, CA-AhR markedly inhibited the growth of Jurkat T cells. The inhibited cell growth was found to be concomitant with both an increase in the annexin V-positive apoptotic cells and the accumulation of cells in the G₁ phase. The growth inhibition was also shown to be mediated by both xenobiotic response element (XRE)-dependent and -independent mechanisms, because an A78D mutant of the CA-AhR, which lacks the ability of XRE-dependent transcription, partially inhibited the growth of Jurkat T cells. Furthermore, we demonstrated that CA-AhR induces expression changes in genes related to apoptosis and cell cycle arrest. These expression changes were shown to be solely mediated in an XRE-dependent manner, because the A78D mutant of the CA-AhR did not induce them. To summarize, these results suggest that AhR activation causes apoptosis and cell cycle arrest, especially through expression changes in genes related to apoptosis and cell cycle arrest by the XRE-dependent mechanism, leading to the inhibition of T cell growth.

Received for publication, February 26, 2004 , and in revised form, March 23, 2004.

^* This work was supported by grants from the Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (to C. T., K. N., T. I., and S. T.) and the Ministry of the Environment. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: National Institute for Environmental Studies, Tsukuba 305-8506, Japan. Tel.: 81-29-850-2500; Fax: 81-29-850-2574; E-mail: keikon{at}nies.go.jp.

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