Synergistic effects of retinoic acid and IL-1beta on expression of the bone-type alkaline phsphatase and retinoid receptors in small intestinal epithelial cells.

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Last year, we reported that simultaneous addition of retinoic acid (RA) and IL-1beta induced a number of proteins as well as liver/bone/kidney alkaline phosphatase (L/B/K ALP) in rat intestinal epithelial IEC-6 cell line. In the subsequent studies, we found that the L/B/K ALP up-regulated with RA and IL-1beta had the bone-type leader sequence, but not liver-type one. Gel mobility shift assay for the putative RXRE showed that the binding activity was synergistically stimulated by the simultaneous treatment with RA and IL-1beta. We further studied the involvement of retinoid receptors and IL-1 receptor in these synergistic effects. The distinct of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) were observed in IEC-6 cells after simultaneous treatment with RA and IL-1beta. RARs alpha and beta, and RXRs alpha and beta were synergistically expressed by RA and IL-1beta, while the expression of RARgamma and RXRgamma were not changed by the simultaneous treatment. The enhancement of RARbeta mRNA expression was the most remarkable among these receptors. It was of interest that IL-1beta increased the mRNA level of RARbeta, but RA itself did not. In contrast, the mRNA level of IL-1 receptor type-I were not changed even after the simultaneous treatment. These finding suggested that up-regulation of retinoid receptors, especially RARbeta, may participated in the synergistic effects of RA and IL-1beta. In a separate experiment, it was also found that simultaneous treatment with RA and IL-1beta synergisticaly increased cathepsin activities in human adenocarcinoma Caco-2 cells. Thus, we will provide the evidence suggesting that IL-1beta may regulate the protein synthesis in intestinal epithelial cells.