title: N-substituted benzamides inhibit nuclear factor-kappaB and nuclear factor of activated T cells activity while inducing activator protein 1 activity in T lymphocytes.
abstract: N-substituted benzamides are compounds that have recently been reported to inhibit nuclear factor-kappaB (NF-kappaB) activity and induce apoptosis in a pre-B cell line. In this study, we focused on the effects of N-substituted benzamides on transcriptional regulation in Jurkat T cells. We used a model system where the cells can be stimulated either through TCR/CD28 or by treatment of the cells with PMA and ionomycin to induce transcription factors typical for T lymphocyte activation. Treatment of the Jurkat cells with procainamide did not influence the transcription factor profile of stimulated cells, while treatment with a derivative having an acetyl group in position 4 of the aromatic ring inhibited NF-kappaB and nuclear factor of activated T cells (NFAT) activity. Declopramide, which contains a chloride in position 3 of the aromatic ring, was inactive in this system, whereas also the acetylated derivative of this compound inhibited NF-kappaB and NFAT activity. In contrast, the transcriptional activity and nuclear expression of activator protein 1 induced by TCR/CD28 stimulation or PMA and ionomycin treatment was enhanced by the acetylated variants of the N-substituted benzamides. Finally, we investigated the effect of N-substituted benzamides on intact promoters for two genes central in immune regulation; the CD40 ligand (CD40L) and IL-2 promoters. The transcriptional activity of the CD40L promoter as well as surface expression of the CD40L induced by signaling through TCR/CD28 was inhibited by addition of acetylated N-substituted benzamides, while the transcriptional activity of the IL-2 promoter was enhanced. Taken together, these data indicate that derivatives of N-substituted benzamides are potential drug candidates for quantitative as well as qualitative modulation of immune functions.
authors.affiliation: Department of Cell and Molecular Biology, Section for Immunology, BMC I:13, Lund University, S-221 84, Lund, Sweden. hanna.lindgren@immuno.lu.se
authors.forename: H
authors.initials: H
authors.lastname: Lindgren
authors.forename: R W
authors.initials: RW
authors.lastname: Pero
authors.forename: F
authors.initials: F
authors.lastname: Ivars
authors.forename: T
authors.initials: T
authors.lastname: Leanderson
mesh_terms: D000120:Acecainide / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D023201:CD40 Ligand / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052002:NF-kappa B p50 Subunit; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011342:Procainamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; D007376:Interleukin-2; C118901:N-acetyldeclopramide; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D023201:CD40 Ligand; D000120:Acecainide; C072799:declopramide; D011342:Procainamide