To investigate which retinoid receptors are critical in the regulation by all-trans-retinoic acid (RA) of the mucin genes MUC2, MUC5AC and MUC5B in cultured normal human tracheobronchial epithelial (NHTBE) cells, we used pan-RAR-, pan-RXR- and RAR- isotype (α, β and γ)-selective agonists and RARα- and RARγ-selective antagonists (RAR is RA receptor and RXR is retinoid X receptor). RAR-, RARα- and RARγ-selective agonists strongly induced mucin mRNAs in a dose-dependent manner, while the RARβ-selective retinoid only weakly induced mucin gene expression at very high concentrations (1 µM). The pan-RXR-selective agonist by itself did not induce mucin gene expression, but acted synergistically with suboptimal concentrations of the pan-RAR agonist. A retinoid with selective anti-activator-protein-1 activity only marginally induced mucin gene expression. The RARα antagonist strongly inhibited mucin gene induction and mucous cell differentiation caused by RA and by the RARα- and RARγ-selective retinoids. In contrast, the RARγ antagonist only weakly inhibited RARα-selective-retinoid-induced mucin gene expression, but completely blocked mucin gene expression induced by the RARγ-selective retinoid. Our studies indicate that RARα is the major retinoid receptor subtype mediating RA-dependent mucin gene expression and mucous cell differentiation, but that the RARγ isotype can also induce mucin genes. Furthermore these studies suggest that RARβ is probably not (directly) involved in RA-induced mucin gene expression.

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