Involvement of Jun and Rel proteins in up-regulation of interleukin-4 gene activity by the T cell accessory molecule CD28.
CD28 serves as a costimulatory cell surface molecule in T cell activation. CD28 signaling may also play a role in balancing the inflammatory/humoral (Th1/Th2) responses during an immune reaction. CD28 costimulation has been shown to promote the production of Th2 cytokines including interleukin (IL)-4, a key cytokine essential for Th2 differentiation and for the pathogenesis of allergic inflammation. In this study, we show that IL-4 mRNA and activity of the IL-4 promoter can be activated by the CD28 signal alone and are further augmented by CD28 costimulation of alpha-CD3- or mitogen-activated Jurkat T cells. Two important IL-4 enhancer elements, positive regulatory element (PRE)-I and P1, are found to respond to CD28 stimulation-induced transactivation. In contrast to the Th1 IL-2 CD28RE, activity of the IL-4 PRE-I and P1 can be induced by the CD28 signal alone. In correlation with CD28-induced transcriptional activation, AP-1 (c-Jun, JunD) and NF-kappaB/Rel (c-Rel, RelA) family members are found to bind to the two regulatory elements PRE-I and P1 upon CD28 stimulation. The data provide the first mapping of the CD28-responsive site in a Th2 cytokine gene, the IL-4 gene. They also show that the CD28 signal can directly activate a gene (e.g. IL-4) at the transcriptional level.
Li-Weber
M
M
Tumor Immunology Program, German Cancer Research Center, D-69126 Heidelberg, Germany. m.li-weber@dkfz-heidelberg.de
Giasi
M
M
Krammer
P H
PH
D001483:Base Sequence; D018106:CD28 Antigens / Q000502:physiology*; D017931:DNA Primers; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics*; D019169:Jurkat Cells; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
D018106:CD28 Antigens; D017931:DNA Primers; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4