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 the normal growth and differentiation of human bronchial epithelial cells. The signaling pathways through which retinoids mediate these effects have not been defined. Insulin-like growth factor binding protein-3 (IGFBP-3) and the transforming growth factor-beta (TGF-beta) gene family (beta 1-3) were examined as potential components of the retinoid signaling pathway in normal human bronchial epithelial cells. All-transretinoic acid (t-RA) increased the levels of TGF-beta 2 and IGFBP-3 mRNA and of secreted TGF-beta and IGFBP-3 proteins. An antagonist of retinoic acid receptor-alpha, LG100629, abrogated the increase in TGF-beta 2 and IGFBP-3 mRNA levels induced by t-RA. t-RA increased IGFBP-3 mRNA levels transiently from 1 to 6 h, and subsequently a sustained increase 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 levels, but treatment with latency-associated peptide, which inactivates secreted TGF-beta, did not abrogate the effect of t-RA on IGFBP-3 expression. These findings provide evidence that t-RA increased TGF-beta 2 and IGFBP-3 expression through an retinoic acid receptor-alpha-dependent pathway, and the increase in IGFBP-3 expression by t-RA did not require activation of the TGF-beta pathway by autocrine or paracrine mechanisms.