Prostanoids in human colonic mucosa: effects of inflammation on PGE 2 receptor expression

Abstract

Although the tissue concentration of PGE 2 is heightened 3-fold or more during mucosal inflammation, the cellular targets of prostanoids in human mucosa and the resulting changes in cell physiology have not been fully explored. We used a panel of immunoglobulin and mRNA probes in order to localize and quantitate the four member EP family of prostanoid receptors for binding PGE 2 to cells of histologically normal and inflamed human colonic mucosa, and then examined prostanoid-induced changes in mucosal lymphocyte function. Prostanoid receptors were selectively expressed on a limited number of human colonic mucosal cells; EP 4 alone was expressed on lamina propria mononuclear cells. Dual immunostaining in situ identified the CD3 + T lymphocyte as a major EP 4 receptor-bearing cell in normal mucosa. Flow cytometry of isolated cells showed that 19.2% of lamina propria mononuclear cells were EP 4 +, and almost 30% of these were CD3 +. In situ hybridization with digoxygenin-labeled RNA probes largely confirmed this localization. During inflammation, mucosal T lymphocytes showed a significant enhancement in EP 4 immunoreactive receptor protein. Computer-assisted densitometry of single cells demonstrated an increase in fluorescence intensity from 4.8 ± 1.8 to 8.6 ± 1.8 ( p < 0.04). The effects of PGE 2 included a 35% reduction in T lymphocyte IL-2 secretion. COX 1 + lamina propria cells nearly doubled in number during inflammation; expressed a T lymphocyte marker; but retained an unchanged quantity of immunoreactive COX 1 protein per cell. The number of newly appeared COX 2 + lymphocytes remained <50% that of COX 1 + cells. A major perturbation in the number and distribution of PGE 2 receptors and enzymes for prostanoid synthesis occurs in chronic inflammation of the colon, with consequences for mucosal T lymphocyte function.