I-kappa B kinases alpha and beta have distinct roles in regulating murine T cell function.
NF-kappaB is a transcription factor that regulates a variety of genes involved in the control of the immune and inflammatory responses. Activation of NF-kappaB is mediated by an inducible I-kappaB kinase (IKK) complex comprised of two catalytic subunits, IKKalpha and IKKbeta. 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-kappaB pathway in thymocytes isolated from these transgenic mice following treatment with either PMA and ionomycin or anti-CD3 was markedly inhibited. Although inhibition of IKKalpha and/or IKKbeta 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 IKKbeta. However, inhibition of both IKKalpha and IKKbeta was required to markedly reduce cytokine production in thymocytes isolated from these transgenic mice. Finally, we demonstrated that IKKalpha and IKKbeta have opposite roles on the regulation of anti-CD3-induced apoptosis of double-positive thymocytes. These results suggest that IKKalpha and IKKbeta have distinct roles in regulating thymocyte function.
Ren
Hong
H
Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Schmalstieg
Aurelia
A
van Oers
Nicolai S C
NS
Gaynor
Richard B
RB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse