Overexpression of mucin genes induced by interleukin-1 beta, tumor necrosis factor-alpha, lipopolysaccharide, and neutrophil elastase is inhibited by a retinoic acid receptor alpha antagonist.
Proinflammatory cytokines, lipopolysaccharide (LPS), and neutrophil elastase (NE) have been implicated in the induction of hypersecretion of respiratory mucus. In this study, we demonstrated that interleukin-1beta (IL-1beta) increased MUC2 and MUC5AC mRNA levels 2- to 3-fold in a time- and dose-dependent manner in NCI-H292 cells. In contrast, MUC5B mRNA was not significantly changed. A transcription inhibitor blocked the stimulation of MUC2 and MUC5AC gene expression by IL-1beta. A translation inhibitor did not interfere with the induction of MUC2 mRNA expression, whereas stimulation of MUC5AC mRNA was blocked, suggesting de novo protein synthesis is required for the stimulation of MUC5AC mRNA. We previously reported that induction of MUC2, MUC5AC, and MUC5B gene expressions by retinoic acid is mediated by the retinoic acid receptor (RARalpha), and inhibited by the specific RARalpha antagonist Ro 41-5253. Here, we demonstrate that the RARalpha antagonist can effectively inhibit IL-1beta-induced MUC2 and MUC5AC gene expression and reduce intracellular MUC5AC protein. Further investigation showed that the RARalpha antagonist also inhibited the stimulation of MUC2 and MUC5AC mRNA expression by tumor necrosis factor-alpha, LPS, and NE.
Koo
Ja Seok
JS
Department of Thoracic Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Kim
Yong-Dae
YD
Jetten
Anton M
AM
Belloni
Paula
P
Nettesheim
Paul
P
D001565:Benzoates / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D001565:Benzoates; D002839:Chromans; D007375:Interleukin-1; D008070:Lipopolysaccharides; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins; D009363:Neoplasm Proteins; C000607071:RARA protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D014409:Tumor Necrosis Factor-alpha; C084904:Ro 41-5253; D019272:Leukocyte Elastase