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Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892 [R. K. P.], and Cytokine Research Section, Department of Clinical Immunology and Biological Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [B. B. A.]
The human immunodeficiency virus type I (HIV-1) regulatory gene, tat III, is a powerful trans-activator of gene expression from the viral long terminal repeat and is essential for HIV replication. In addition, tat III protein has been shown to be immunosuppressive as indicated by the inhibition of antigen mediated T-cell proliferation. To further test whether tat III might play a direct role in the immunosuppressive effects of HIV-1 in addition to its role in virus replication, we examined the regulation of interleukin 4 (IL-4) receptors on a human B-lymphoblastoid cell line (Raji) transfected with HIV-1 tat gene (Raji-tat III). We used radioligand receptor binding analysis for cell surface expression and Northern blot analysis for the expression of human IL-4 receptor gene in Raji-tat III cells. Control Raji cells expressed 1383 ± 361 (SE; n = 3) IL-4 binding sites/cell with a dissociation constant (Kd) of 144 ± 27 pM (n = 3). However, Raji-tat III cells expressed about three times higher IL-4 receptors (4000 ± 633 IL-4 binding sites/cell; P < 0.03 compared to Raji cells) with a similar Kd of 273 ± 90 pM (n = 3; P > 0.05 compared to Raji cells). Whereas both Raji and Raji-tat III cells exhibited a single mRNA species (approximately 4 kilobases) of IL-4 receptors by Northern blot analysis, the mRNA level was about 3-fold higher in Raji-tat III cells compared to Raji cells. Cycloheximide inhibited the expression of IL-4 receptors by 50% in about 2 h in both cell types indicating both the half-life of IL-4 receptors and the requirement for protein synthesis for the tat III up-regulation of IL-4 receptors. Since IL-4 under certain circumstances has been shown to be immunosuppressant, our observation that the HIV-1 tat gene up-regulates IL-4 receptors suggests the possibility that the immunosuppressive effects of HIV-1 are mediated at least in part through IL-4 receptors.
1 To whom requests for reprints should be addressed, at Laboratory of Cellular Immunology, Division of Cytokine Biology, CBER/FDA, NIH-Building 29A, Room 2B20, 8800 Rockville Pike, Bethesda, MD 20892.
Received 3/19/92. Accepted 5/13/92.
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