RETINOIC ACID RECEPTOR-SELECTIVE AND RETINOID-X RECEPTOR-SELECTIVE RETINOIDS ACTIVATE SIGNALING PATHWAYS THAT CONVERGE ON AP-1 AND INHIBIT SQUAMOUS DIFFERENTIATION IN HUMAN BRONCHIAL EPITHELIAL-CELLS

Human bronchial epithelial (HBE) cells undergo squamous differentiatio n in response to a variety of conditions in tissue culture, and retino id treatment has been shown to reverse this process. Retinoids mediate their effects through the retinoic acid and retinoid X nuclear recept ors (RAR and RXR, respectively), which form RAR-RXR heterodimers, RXR homodimers, and heterodimers of RXR and certain orphan receptors. Thes e receptor dimers bind to distinct response elements, activating separ ate pathways. In this study, we investigated the roles of RAR and RXR signaling pathways in the inhibition of HBE squamous differentiation. After induction of squamous differentiation by confluent growth, HBE c ells were treated with retinoids that selectively activate RARs ,7,8-t etrahydro-2-naphthalenyl)-1-propenyl]benzoic acid), RXRs thyl-5,6,7,8- tetrahydro-2-naphthyl)ethenyl]benzoic acid), or both RARs and RXRs (9- cis retinoic acid). These retinoids inhibited the mRNA expression of t he squamous differentiation markers transglutaminase type I, involucri n, keratin 5, and keratin 13, suggesting that inhibition of HBE squamo us differentiation could be mediated by activation of either RAR or RX R signaling pathways. We examined the role of AP-1 as a potential effe ctor of these retinoid pathways. AP-1 transcriptional activity was red uced markedly by these retinoids, and a concomitant, but proportionall y smaller, reduction in AP-1 DNA binding was observed. Furthermore, tr eatment of squamous HBE cells with the retinoid SR11238, which inhibit ed AP-1 without activating retinoid receptor transcriptional propertie s, reduced the expression of transglutaminase type I and involucrin. T hese findings support the hypothesis that, in HBE cells, RAR and RXR s ignaling pathways inhibit AP-1 transcriptional activity, and this cont ributes to retinoid-induced reversal of HBE squamous differentiation.