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I-B Kinases and Have Distinct Roles in Regulating Murine T Cell Function¹

Hong Ren^*, Aurelia Schmalstieg^*, Nicolai S. C. van Oers and Richard B. Gaynor^2,*

^* Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, and Center for Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390

NF-B is a transcription factor that regulates a variety of genes involved in the control of the immune and inflammatory responses. Activation of NF-B is mediated by an inducible I-B kinase (IKK) complex comprised of two catalytic subunits, IKK and IKK. In this study, the role of these kinases in the development and function of T lymphocytes was explored using transgenic mice expressing the dominant-negative forms of one or both kinases under the control of a T cell-specific promoter. Activation of the NF-B pathway in thymocytes isolated from these transgenic mice following treatment with either PMA and ionomycin or anti-CD3 was markedly inhibited. Although inhibition of IKK and/or IKK function did not alter T cell development in these transgenic mice, the proliferative response to anti-CD3 was reduced in thymocytes isolated from mice expressing dominant-negative IKK. However, inhibition of both IKK and IKK was required to markedly reduce cytokine production in thymocytes isolated from these transgenic mice. Finally, we demonstrated that IKK and IKK have opposite roles on the regulation of anti-CD3-induced apoptosis of double-positive thymocytes. These results suggest that IKK and IKK have distinct roles in regulating thymocyte function.

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