title: Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes.
abstract: Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.
mesh_terms: D002135:Calcium-Binding Proteins / Q000378:metabolism; D040501:Calgranulin A; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D007633:Keratins / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000494:pharmacology; D009281:Naphthalenes / Q000378:metabolism* / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011503:Transglutaminases / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma