Pentoxifylline inhibits HIV-1 LTR-driven gene expression by blocking NF-kappa B action.
The drug pentoxifylline (PTX) (1-(5'-oxohexyl) 3,7-dimethylxanthine) down-regulates human immunodeficiency virus (HIV-1) long terminal repeat (LTR)-directed gene expression in the human monocytic cell line U38. This effect of PTX has been tested in clinical trials. In this investigation, a similar inhibitory effect of PTX on HIV-1 LTR-driven gene expression was observed (a) in a stable transfectant of the human embryo kidney cell line 293-27-2 carrying an expression plasmid construct with the HIV-1 LTR fused to the bacterial lac Z gene, and also (b) by transient transfection of human embryo kidney cells 293 S with fusion plasmid constructs with wild-type [pHIV-LTR-chloramphenicol acetyltransferase (CAT)] or mutated (pHIV-LTR-mut-CAT) nuclear factor kappa B (NF-kappa B) motifs. In both stable and transient transfection studies, 4-beta-phorbol-12-beta-myristate-acetate (PMA)-induced or tumor necrosis factor-alpha (TNF-alpha)-induced activation of the HIV-1 LTR was correlated with a concomitant elevated level of NF-kappa B interaction with its motifs. The inducibility of HIV-1 LTR-driven gene expression by PMA or TNF-alpha in transiently transfected cells was completely eliminated by point mutations in the NF-kappa B motifs, suggesting that NF-kappa B plays a major role in the activation of the HIV-1 LTR by these agents in this cell system.(ABSTRACT TRUNCATED AT 250 WORDS)
Biswas
D K
DK
Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Boston, MA 02115.
Dezube
B J
BJ
Ahlers
C M
CM
Pardee
A B
AB
D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D010431:Pentoxifylline / Q000494:pharmacology*; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012045:Regulatory Sequences, Nucleic Acid; D012091:Repetitive Sequences, Nucleic Acid / Q000502:physiology; D014162:Transfection
D016328:NF-kappa B; D009841:Oligonucleotides; D010431:Pentoxifylline