Pentoxifylline and other protein kinase C inhibitors down-regulate HIV-LTR NF-kappa B induced gene expression

D K Biswas, C M Ahlers, B J Dezube, A B Pardee
Molecular Medicine 1994, 1 (1): 31-43

BACKGROUND: This investigation deals with the molecular mechanism of anti-human immunodeficiency virus type 1 (HIV-1) action of pentoxifylline (PTX) [1-(5'-oxohexyl)-3, 7-dimethylxanthine] a drug widely used for the treatment of conditions involving defective regional microcirculation.

MATERIALS AND METHODS: The inhibition by PTX of protein kinase C (PKC) or cAMP-dependent protein kinase (PKA)-mediated activation by phorbol ester (PMA) and tumor necrosis factor alpha (TNF-alpha) of HIV-1-LTR-regulated reporter gene expression was studied in human CD4+ T lymphocytes (Jurkat) and human embryo kidney cells (293-27-2). A protein kinase C is involved in activation of NF-kappa B in whole cells, identified by using inhibitors specific for PKC- or PKA-catalyzed NF-kappa B activation in whole cell and cell-free systems.

RESULTS: PTX inhibited PKC- or PKA-catalyzed activation of NF-kappa B in cytoplasmic extracts from unstimulated Jurkat or 293-27-2 cells, but not interaction of preactivated NF-kappa B with its motifs. Calphostin C, a specific inhibitor of PKC, inhibited NF-kappa B activation and HIV-1 LTR-driven reporter gene expression in both PMA- and TNF-alpha-treated cells. In contrast, although H88 specifically inhibited PKA activity in the cell-free extract, it did not affect NF-kappa B action in PMA- or TNF-alpha-treated cells.

CONCLUSIONS: The mechanism of inhibitory action of PTX on virus replication and NF-kappa B-induced transactivation of HIV-1 gene expression has been elucidated as due to blocking PKC-dependent PMA- or TNF-alpha-induced activation of NF-kappa B in Jurkat and 293-27-2 cells. Other protein kinase inhibitors may be useful in down regulating transcription of HIV-1 provirus and thereby virus replication in HIV-infected patients.

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