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 replication. We have reported that the HIV-1 tat gene can up-regulate interleukin 4 receptors (IL-4R) however, the mechanism of this up-regulation is not understood. We now show that in Raji cells, 125I-labeled IL-4 cross-linked to three proteins of 140, 70, and 63 kDa, which were immunoprecipitated with an antibody to the human IL-4R. Although this level of all three IL-4 binding proteins increased in tat-transfected cells, the binding characteristics of IL-4R on control or mock transfected control and tat-transfected cells remained similar. The exogenous recombinant Tat protein or supernatant of tat transfected Raji cells also up-regulated the expression of the IL-4R on two renal cell carcinoma cell lines in a concentration-dependent manner. The actinomycin D chase experiments revealed that the half-lives of the IL-4R protein (t1/2 3.5 hr) and mRNA transcripts (t1/2 2.5 hr) were similar in both control and tat-transfected cells. In contrast, nuclear run-on experiments revealed that the rate of the IL-4R mRNA transcription increased 3- to 5-fold in Raji-tat compared to Raji cells. These data indicate that the HIV-1 tat gene up-regulates IL-4R expression by increasing the transcription rate rather than posttranscriptional stabilization of either the mRNA or the protein. HIV-tat inducible exogenous tumor necrosis factor (TNF-alpha) did not up-regulate IL-4R and IL-4R inducible activation of signal transducers and activators of transcription (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 directly with the IL-4R gene and up-regulate IL-4R transcription.
Laboratory of Molecular Tumor Biology, FDA, Bethesda, Maryland 20892, USA.
S R
SR
Husain
P
P
Leland
B B
BB
Aggarwal
R K
RK
Puri
D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D015696:Gene Products, tat / Q000235:genetics / Q000494:pharmacology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus
D015703:Antigens, CD; D015696:Gene Products, tat; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D003609:Dactinomycin; D015847:Interleukin-4