ALL-TRANS-RETINOIC ACID INCREASES TRANSFORMING GROWTH-FACTOR-BETA-2 AND INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-3 EXPRESSION THROUGH A RETINOIC ACID RECEPTOR-ALPHA-DEPENDENT SIGNALING PATHWAY

Retinoids, including retinol and retinoic acid derivatives, maintain t he normal growth and differentiation of human bronchial epithelial cel ls. The signaling pathways through which retinoids mediate these effec ts have not been defined. Insulin-like growth factor binding protein-3 (IGFBP-3) and the transforming growth factor-beta (TGF-beta) gene fam ily (beta 1-3) were examined as potential components of the retinoid s ignaling pathway in normal human bronchial epithelial cells. All-trans retinoic acid (t-RA) increased the levels of TGF-beta 2 and IGFBP-3 mR NA and of secreted TGF-beta and IGFBP-3 proteins. An antagonist of ret inoic acid receptor-alpha, LG100629, abrogated the increase in TGF-bet a 2 and IGFBP-3 mRNA levels induced by t-RA. t-RA increased IGFBP-3 mR NA levels transiently from 1 to 6 h, and subsequently a sustained incr ease began at 72 h, which coincided with the appearance of active TGF- beta in the media. Treatment with TGF-beta 2 increased IGFBP-3 mRNA le vels, but treatment with latency-associated peptide, which inactivates secreted TGF-beta, did not abrogate the effect of t-RA on IGFBP-3 exp ression. These findings provide evidence that t-RA increased TGF-beta 2 and IGFBP-3 expression through an retinoic acid receptor-alpha-depen dent pathway, and the increase in IGFBP-3 expression by t-RA did not r equire activation of the TGF-beta pathway by autocrine or paracrine me chanisms.