Overexpression of p65 and c-Jun substitutes for B7-1 costimulation by targeting the CD28RE within the IL-2 promoter.
The role of Rel and activation protein-1 (AP-1) in IL-2 promoter activity in B7-1- and leukocyte function-associated Ag-3 (LFA. 3)-costimulated T cells has been evaluated. We demonstrate that overexpression of c-Jun but not c-Fos increases IL-2 promoter activity in both B7-1- and LFA-3-costimulated Jurkat T cells. Cotransfection of both c-Jun and c-Fos substitutes for B7-1 costimulation in driving an activation protein-1 response element but not for the IL-2 promoter. Overexpression of Rel proteins demonstrated that p65-expressing Jurkat cells transcribed equally well a nuclear factor kappabeta reporter construct when costimulated with B7-1 or LFA-3, but transcription of IL-2 promoter or CD28 response element (CD28RE)-driven reporters was superior in B7-1-costimulated cells. Combined expression of c-Jun and p65 induced vigorous transcription of IL-2 promoter- and CD28RE-driven reporter constructs in both LFA-3- and B7-1-costimulated Jurkat cells. Mutating the CD28RE but not the upstream nuclear factor kappabeta-binding site in the IL-2 promoter reduced B7-1-driven transcription >90%. The results implicates a major role of the CD28RE in the integration of p65/c-Jun-mediated transcription within the IL-2 promoter. We suggest that the transition from an autocrine LFA-3-driven immune response to a B7--induced paracrine immune response involves the activation of c-Jun and p65, which target the CD28RE region of the IL-2 promoter.
Parra
E
E
Department of Cell and Molecular Biology, University of Lund, Sweden.
McGuire
K
K
Hedlund
G
G
Dohlsten
M
M
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D018122:B7-1 Antigen / Q000502:physiology*; D018106:CD28 Antigens / Q000235:genetics*; D018968:CD58 Antigens / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics*; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000502:physiology; D018089:Superantigens / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000276:immunology; D014162:Transfection / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D018106:CD28 Antigens; D018968:CD58 Antigens; D007376:Interleukin-2; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018089:Superantigens; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA