Tat is a transcription transactivator produced by the human immunodeficiency virus type 1 (HIV-1) at the early phase of infection and plays a critical role in the expression and replication of the viral genome. This 86 amino acid protein, which can be secreted from the infected cells, has the ability to enter uninfected cells and exert its activity upon the responsive genes. Earlier results indicated that in addition to the HIV-1 promoter, Tat has the capacity to induce transcription of a variety of cellular genes. In this study, we demonstrate that exposure of cells from the central nervous system (U-87MG and SK-N-MC) and the lymphoid T cells (Jurkat) to highly purified Tat increases transcriptional activity of the reporter constructs containing the promoters from the transforming growth factor beta-1 (TGFbeta-1), the tumor necrosis factor alpha (TNFalpha), and the HIV-1 LTR. In addition, Tat treatment results in increased levels of TGFbeta-1 and TNFalpha mRNAs in these cells. Activation of the TGFbeta-1 and TNFalpha promoter constructs by Tat in U-87MG and SK-N-MC cells required amino acid residues 2 to 36 which spans the acidic and the cysteine-rich domains of Tat. In both CNS and lymphoid cells, the level of endogenous TGFbeta-1 mRNA was increased by mutant Tat protein containing amino acids 1 to 48 but not with a mutant Tat protein with a deletion between residues 2 to 36. TNFalpha mRNA level was increased by mutant Tat spanning residues 1 to 48 in U-87MG cells, but not in SK-N-MC and Jurkat cells. These observations suggest that activation of cellular and viral genes by Tat in various cells may be mediated by different pathways as evidenced by the requirements of the different regions of Tat. Activation of the TGFbeta-1 and TNFalpha promoters by wild-type Tat was severely affected by the mutant peptides spanning residues 2 to 36 and 1 to 48 suggesting that both truncated Tat peptides may function as dominant negative mutants over TNFalpha and TGFbeta-1 gene transcription. The importance of these findings in Tat-induced regulation of viral and cellular genes in various cell types is discussed.