Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chemokine that blocks HIV infection.
The complex network of cytokines that are involved in inflammatory and immunoregulatory responses plays a critical role in the pathogenesis of HIV infection. RANTES (regulated upon activation, normal T cell expressed and secreted) is a cytokine that belongs to the beta-chemokine family; it is chemoattractant for CD4+/CD45RO T cells, it is produced by various cell types including CD8+ and CD4+ T cells as well as monocytes/macrophages, and has recently been shown to suppress replication of macrophage-tropic strains of HIV in CD4+ T cells. To investigate the molecular mechanisms of RANTES expression, the RANTES promoter region was analyzed by transient expression and gel-mobility shift assays. We demonstrate that: 1) RANTES promoter activity is up-regulated by PMA plus ionomycin, coexpression of the p65 subunit of nuclear factor (NF)-kappa B, the proinflammatory cytokines TNF-alpha and IL-1 beta, and the CD28 costimulatory pathway; 2) the RANTES promoter region contains four NF-kappa B binding sites at positions -30, -44, -213, and -579 relative to the transcription start site; 3) one site (-213) is an NF-AT (nuclear factor of activated T cells) binding site that also has weak affinity to NF-kappa B, and the most distal site (-579) also serves as a CD28-responsive element; and 4) mutation on any of those NF-kappa B sites or coexpression of I kappa B alpha (cytoplasmic inhibitor of NF-kappa B) markedly reduced the promoter activity. Thus, NF-kappa B, a potent transcriptional activator of HIV expression, is also involved in the expression of RANTES, a chemokine that blocks infection by macrophage-tropic strains of HIV.
Moriuchi
H
H
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Moriuchi
M
M
Fauci
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AS
D001665:Binding Sites; D018106:CD28 Antigens / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D018946:Chemokine CCL5 / Q000235:genetics* / Q000494:pharmacology*; D016384:Consensus Sequence; D015658:HIV Infections / Q000235:genetics / Q000517:prevention & control*; D006567:Herpesvirus 2, Saimiriine / Q000276:immunology; D006801:Humans; D016328:NF-kappa B / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D018106:CD28 Antigens; D018946:Chemokine CCL5; D016328:NF-kappa B; D012333:RNA, Messenger; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha