2-cyano-3-(1-phenylindol-3-yl)acrylate and tenidap

Interleukin-6 (IL-6) may be important in the pathogenesis of HIV-1 because of its ability to induce HIV-1 expression in infected cells in vitro. Tenidap, a structurally and functionally novel antirheumatic drug affecting diverse biologic processes, has been shown to reduce IL-6 production by peripheral blood mononuclear cells stimulated with lipopolysaccharide. Tenidap also inhibits the activity of chloride-bicarbonate exchangers and causes acidification of the cytoplasmic compartment that is similar to the effect of the anion transport inhibitor UK5099. Furthermore, tenidap inhibits the cyclooxygenase-mediated pathway of arachidonic acid metabolism as do the nonsteroidal antiinflammatory drugs (NSAIDs). Here we show that tenidap decreased HIV-1 replication as measured by p24 core antigen in the acutely infected CD4+ T-lymphocyte lines H9 and Jurkat, in the acutely infected monocyte line U937, and in its chronically infected subclone U1.8/HIV. These effects were seen at concentrations in the range of 3 to 15 microM, well below those toxic to cells. The antiviral effects of tenidap may be independent of its ability to reduce IL-6 production based on the observations that these effects were as prominent in IL-6 nonresponsive lines as in IL-6 responsive lines and that the inhibition of p24 production was not reversed by exogenous IL-6.

Topics: Acrylates; Anti-Inflammatory Agents, Non-Steroidal; CD4-Positive T-Lymphocytes; Cell Line; Cell Survival; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; HIV Core Protein p24; HIV-1; Humans; Hydrogen-Ion Concentration; Indoles; Interleukin-6; Jurkat Cells; Lethal Dose 50; Monocytes; Oxindoles; Piroxicam; Virus Replication

The production of interleukin-1beta (IL-1beta), a powerful mediator of inflammation, is tightly regulated at several levels. However, in some pathologic conditions, a pharmacologic treatment is required to control the toxicity of excessive extracellular IL-1beta. Because of the heavy side effects of most therapies used in IL-1beta-mediated pathologies, a goal of pharmacologic research is the development of selective anti-IL-1beta drugs. We show here that the sulfonylurea glyburide, currently used in the oral therapy of noninsulin dependent diabetes, is an inhibitor of IL-1beta secretion from human monocytes and mouse macrophages. Glyburide reduces dramatically the recovery of extracellular 17-kD IL-1beta in the absence of toxic effects on the cells and without affecting the synthesis or processing of the IL-1beta precursor. IL-1beta belongs to the family of leaderless secretory proteins released from the cell by a nonclassical secretory route. In bacteria and yeast Atp binding cassette (ABC) transporters are involved in the secretion of leaderless secretory proteins. Interestingly, glyburide blocks the anion exchanger function of ABC1, a mammalian member of the family of ABC transporters. We thus investigated the involvement of ABC1 in IL-1beta secretion, through the analysis of the effects of drugs known to inhibit IL-1beta secretion, on the activity of ABC1 and in turn the ability of known inhibitors of ABC1 of blocking IL-1beta secretion. Our data show that IL-1beta secretion and the function of ABC1 as an anion exchanger are sensitive to the same drugs, therefore suggesting an involvement of the ABC1 transporter in the secretion of leaderless proteins in mammals.

Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Acrylates; Adenosine Triphosphate; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Calcium Channel Blockers; Caspase 1; Cells, Cultured; Cysteine Endopeptidases; Glyburide; Glycoproteins; Humans; Hypoglycemic Agents; Indoles; Interleukin-1; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred CBA; Monocytes; Oxindoles; Recombinant Proteins; Verapamil; Xenopus laevis