title: IkappaB kinases serve as a target of CD28 signaling.
abstract: Optimal T cell activation and interleukin-2 production requires a second signal in addition to antigen-mediated T cell receptor (TCR) signaling. The CD28 molecule has been demonstrated to act as an effective costimulatory molecule upon binding by B7.1 or B7.2 present on antigen-presenting cells. The CD28 signal acts in concert with the TCR signal to significantly augment activation of the NF-kappaB family of transcription factors. The interleukin-2 gene is regulated by NF-kappaB among other transcription factors, in part, via a CD28 responsive element (CD28RE) present in the IL-2 promoter. Enhanced activation of NF-kappaB by CD28 is mediated by rapid phosphorylation and proteasome-mediated degradation of the NF-kappaB inhibitory proteins IkappaB alpha and IkappaB beta, which allows for accelerated nuclear expression of the liberated NF-kappaB. Herein, we provide evidence that the catalytic activities of two recently identified IkappaB kinases, IKKalpha and IKKbeta, are significantly elevated when T cells are stimulated through CD28 in addition to mitogen treatment. Catalytically inactive forms of IKKs are able to block the in vivo phosphorylation of IkappaB alpha induced by mitogen and CD28. Furthermore, CD28-mediated reporter gene transactivation of the CD28RE/AP-1 composite element is consistently attenuated by the IKK mutants. These findings suggest that cellular signaling pathways initiated at the TCR and CD28 converge at or upstream of IKK, resulting in more robust kinase activity and enhanced and prolonged NF-kappaB activation.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Harhaj
authors.forename: S C
authors.initials: SC
authors.lastname: Sun
mesh_terms: D018106:CD28 Antigens / Q000378:metabolism*; D002384:Catalysis; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human