Superinduction of IL-8 in T cells by HIV-1 Tat protein is mediated through NF-kappaB factors.
Elevated levels of circulating IL-8, a potent chemotactic factor for granulocytes and T lymphocytes, are found in HIV-infected individuals. The HIV-1 transactivator protein Tat increased IL-8 secretion in T cell lines following CD3- and CD28-mediated costimulation. Full-length Tat (Tat101) enhanced IL-8 transcription through up-regulated transcription factor binding to the CD28-responsive element (CD28RE) in the IL-8 promoter. Expression of the Tat splice variant Tat72 (72 amino acids) also enhanced IL-8 production following T cell stimulation via a different, most likely post-transcriptional, mechanism. The CD28RE in the IL-8 promoter was characterized as a low-affinity NF-kappaB binding site recognized by the transcription factors p50 (NF-kappaB1), p65 (RelA) and c-rel. Transcription factor binding to "classical" NF-kappaB sites in the HIV-1, the human IL-2, and lymphotoxin promoters, recognized by p50 and p65 following CD3+28-mediated costimulation, was unaffected by Tat101 as was binding to the AP-1 motif in the IL-8 promoter. These experiments identify the CD28RE in the IL-8 promoter as a c-rel recognition site and a Tat101-responsive element. The effect of Tat101 on CD28REs in the IL-8 promoter and the subsequent up-regulation of IL-8 secretion is likely to contribute to the immune dysregulation observed during HIV-1 infection.
Ott
M
M
The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Lovett
J L
JL
Mueller
L
L
Verdin
E
E
D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D002478:Cells, Cultured; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus
D018106:CD28 Antigens; D017252:CD3 Complex; D015696:Gene Products, tat; D007376:Interleukin-2; D016209:Interleukin-8; D016328:NF-kappa B; D054322:tat Gene Products, Human Immunodeficiency Virus