TRANSCRIPTIONAL UP-REGULATION OF INTERLEUKIN-4 RECEPTORS BY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT GENE

The human immunodeficiency virus type 1 (HIV-1) regulatory gene, tat, encodes an early transactivator protein (Tat) necessary for virus repl ication, We have reported that the HIV-1 tat gene can up-regulate inte rleukin 4 receptors (IL-4R) however, the mechanism of this up-regulati on is not understood, We now show that in Raji cells, I-125-labeled IL -4 cross-linked to three proteins of 140, 70, and 63 kDa, which were i mmunoprecipitated with an antibody to the human IL-4R. Although this l evel of all three IL-4 binding proteins increased in tat-transfected c ells, the binding characteristics of the IL-4R on control or mock tran sfected control and tat-transfected cells remained similar, The exogen ous recombinant Tat protein or supernatant of tat transfected Raji cel ls also up-regulated the expression of the IL-4R on two renal cell car cinoma cell lines in a concentration-dependent manner. The actinomycin D chase experiments revealed that the half-lives of the IL-4R protein (t(1/2) 3.5 hr) and the mRNA transcripts (t(1/2) 2.5 hr) were similar in both control and tat-transfected cells, In contrast, nuclear run-o n experiments revealed that the rate of the IL-4R mRNA transcription i ncreased 3- to 5-fold in Raji-tat compared to Raji cells, These data i ndicate that the HIV-1 tat gene up-regulates IL-4R expression by incre asing the transcription rate rather than posttranscriptional stabiliza tion of either the mRNA or the protein, HIV-tat inducible exogenous tu mor necrosis factor (TNF-alpha) did not up-regulate IL-4R and IL-4 ind ucible activation of signal transducers and activators of transcriptio n (STAT-6) was not observed by Tat even though IL-4R were up-regulated , These results allow us to speculate that HIV-1 tat may interact dire ctly with the IL-4R gene and up-regulate IL-4R transcription.