INHIBITION OF IFN-GAMMA ACTIVITY IN SUPERNATANTS FROM STIMULATED HUMAN INTESTINAL MONONUCLEAR-CELLS PREVENTS UP-REGULATION OF THE POLYMERICIG RECEPTOR IN AN INTESTINAL EPITHELIAL-CELL LINE

The polymeric IgR (plgR) mediates transcytosis of polymeric IgA across mucosal epithelia. Expression of this receptor in HT-29.74 human colo n carcinoma cells is up-regulated by the recombinant cytokines IFN-gam ma, TNF-alpha, and IL-4. Here, we demonstrate that activation of fresh ly isolated human intestinal lamina propria mononuclear cells (LPMC) i nduces production of natural cytokines, and these act synergistically as potent stimulators of plgR expression in HT-29.74 cells. LPMC from normal colonic mucosa were stimulated with PMA and calcium ionophore A -23187. The resulting supernatants consistently induced dose-dependent increases in plgR expression by HT-29.74 cells, up to 65-iold. Analys is of four separate LPMC supernatants revealed mean concentrations of 8260 pg/ml for IFN-gamma, 420 pg/ml for TNF-alpha, and 15-pg/ml for IL -4. Ab-mediated neutralization of these cytokines suggested that the c entral regulator of plgR expression in these supernatants was IFN-gamm a. IL-4 neutralization had no effect on induction and TNF-cr neutraliz ation slightly reduced induction. In contrast, IFN-gamma neutralizatio n abolished up to 93% of plgR induction and had essentially the same e ffect as simultaneous neutralization of all three cytokines. In conclu sion, our data demonstrate that natural cytokines, predominantly IFN-g amma, produced by stimulated human intestinal lymphocytes and macropha ges have the capacity to up-regulate dramatically plgR expression in a n intestinal epithelial cell line, strongly suggesting that their acti on in vivo leads to enhancement of local defense functions mediated by IgA.