REGULATION OF HUMAN CACO-2 INTESTINAL EPITHELIAL BRUSH-BORDER ENZYME-ACTIVITY BY CYCLIC-NUCLEOTIDES

Regulation of intestinal epithelial differentiation is critical to nor mal function, malignant transformation, and healing. However, the intr acellular regulation of intestinal epithelial differentiation is incom pletely understood. We studied the effects of intracellular cyclic AMP and cyclic GMP on brush border enzyme activity in the human Caco-2 in testinal epithelial cell using pharmacologic agonists and antagonists of cAMP and cGMP mediated pathways as probes. The stable cyclic nucleo tide analogs dibutyryl cAMP and dibutyryl cGMP selectively decreased C aco-2 dipeptidyl dipeptidase specific activity while increasing alkali ne phosphatase. The inhibitors of adenylate and guanylate cyclase KT57 20 and KT5823 each exerted the opposite effects. Combinations of dibut yryl cAMP and dibutyryl cGMP demonstrated synergistic effects on each brush border enzyme but KT5720 and KT5823 were less than additive. Thu s, cAMP and cGMP may regulate human intestinal epithelial differentiat ion by interacting pathways.