TRANSFORMING GROWTH-FACTOR-BETA AND IL-1-BETA ACT IN SYNERGY TO ENHANCE IL-6 SECRETION BY THE INTESTINAL EPITHELIAL-CELL LINE, IEC-6

Intestinal epithelial cells are a potentially important source for a number of cytokines that may modulate the immune response at the intestinal mucosa. We have recently begun to study the mechanisms that regulate IL-6 production by intestinal epithelial cells using the nontransformed crypt-like rat intestinal epithelial cell line IEC-6 as a model. Culture of the IEC-6 cells with human rIL-1beta resulted in an enhanced secretion of IL-6 by the cells. RT-PCR analysis of IL-1beta-treated cells showed an enhanced level of IL-6 mRNA at 4 h, suggesting that IL-1beta enhanced IL-6 gene expression. In a previous study, transforming growth factor-beta (TGF-beta1) was also found to enhance IL-6 secretion by the IEC-6 cells and because both IL-1beta and TGF-beta may be present in inflamed mucosal tissue, the effect of adding both cytokines together was next investigated. Culture of the IEC-6 cells with both TGF-beta1 and IL-1beta resulted in a synergistic enhancement of IL-6 secretion that was seen even at high levels of both TGF-beta and IL-1beta. IL-6 mRNA levels from cells treated with both TGF-beta1 and IL-1beta were also determined to be enhanced when compared to that of cells treated with IL-1beta or TGF-beta1 only, as determined by RT-PCR analysis. Pretreatment of the IEC-6 cells with TGF-beta1 for 2 or 3 days before addition of the IL-1beta induced the IEC-6 cells to differentiate and become more sensitive to stimulation by IL-1beta. Subsequent experiments determined that TGF-beta enhanced the capacity of the IEC-6 cells to bind labeled IL-1beta indicating that TGF-beta may have enhanced the expression of IL-1 receptors on the cells. These results suggest that the intestinal epithelial cell may represent an important source of IL-6 in inflammatory responses at the intestinal mucosa and that TGF-beta could potentiate this function.