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Pentoxifylline and Other Protein Kinase C Inhibitors Down-Regulate HIV-LTR NF-κB Induced Gene Expression

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Abstract

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-α) 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-κB in whole cells, identified by using inhibitors specific for PKC- or PKA-catalyzed NF-κB activation in whole cell and cell-free systems.

Results

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

Conclusions

The mechanism of inhibitory action of PTX on virus replication and NF-κB-induced trans-activation of HIV-1 gene expression has been elucidated as due to blocking PKC-dependent PMA- or TNF-α-induced activation of NF-κB 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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Acknowledgments

The authors thank Dr. L. A. Herzenberg of Standard University for providing the 293-27-2 cells. This research was supported by grants from Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ, U.S.A., and by a Center for AIDS Research Award to the Dana-Farber Cancer Institute. B.J.D. is a Clinical Oncology Career Development awardee of the American Cancer Society.

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Authors and Affiliations

  1. Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Dana-810, 44 Binney Street, Boston, Massachusetts, 02115, USA

    Debajit K. Biswas

  2. Harvard Medical School, Boston, Massachusetts, USA

    Christoph M. Ahlers, Bruce J. Dezube & Arthur B. Pardee

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Biswas, D.K., Ahlers, C.M., Dezube, B.J. et al. Pentoxifylline and Other Protein Kinase C Inhibitors Down-Regulate HIV-LTR NF-κB Induced Gene Expression. Mol Med 1, 31–43 (1994). https://doi.org/10.1007/BF03403529

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