Effects of human immunodeficiency virus type 1 Tat protein on expression of inflammatory cytokines by human astrocytic and monocytic cells

Abstract

Effects of recombinant $\rm Tat\sb{1-72}$ on the expression of inflammatory cytokines were investigated using a human monocytic cell line (THP-1) and a human astrocytoma cell line (U373 MG). Tat induced a differential expression of mRNA for cytokines interleukin-$1\beta$ (IL-$1\beta),$ interleukin-6 (IL-6) and tumor necrosis factor-$\alpha$ (TNF-$\alpha)$ in THP-1 and U373 cells. The increases in gene transcriptions lead to corresponding increases in the production of cytokine proteins in THP-1 cells. However, in U373 cells, Tat only induced production of IL-6 protein while the inductions of IL-$1\beta$ and TNF-$\alpha$ proteins by Tat were not observed. To determine the mechanism(s) by which Tat induced the expression of cytokines, we first examined the role of nuclear factor kappa B (NF-$\rm\kappa B).$ Tat-induced expression of IL-$1\beta$ and IL-6 in U373 cells, and IL-$1\beta$ and TNF-$\alpha$ in THP-1 cells were completely blocked by an inhibitor of NF-$\rm\kappa B$ activation (TLCK), indicating that NF-$\rm\kappa B$ mediates Tat induced-cytokine production. Further the inhibition of phospholipase C (PLC), protein tyrosine kinase (PTK) or protein kinase A (PKA) blocked the expression of IL-$1\beta$ and TNF-$\alpha.$ Whereas inhibition of protein kinase C (PKC) had no effect on Tat induction of cytokine expression, suggesting that PLC, PKA and PTK are involved in Tat induced expression of the cytokines probably through activating NF-$\rm\kappa B.$