Inhibition of IFN-gamma activity in supernatants from stimulated human intestinal mononuclear cells prevents up-regulation of the polymeric Ig receptor in an intestinal epithelial cell line.

Abstract

The polymeric IgR (pIgR) mediates transcytosis of polymeric IgA across mucosal epithelia. Expression of this receptor in HT-29.74 human colon carcinoma cells is up-regulated by the recombinant cytokines IFN-gamma, TNF-alpha, and IL-4. Here, we demonstrate that activation of freshly isolated human intestinal lamina propria mononuclear cells (LPMC) induces production of natural cytokines, and these act synergistically as potent stimulators of pIgR 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 pIgR expression by HT-29.74 cells, up to 65-fold. Analysis 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 central regulator of pIgR expression in these supernatants was IFN-gamma. IL-4 neutralization had no effect on induction and TNF-alpha neutralization slightly reduced induction. In contrast, IFN-gamma neutralization abolished up to 93% of pIgR induction and had essentially the same effect as simultaneous neutralization of all three cytokines. In conclusion, our data demonstrate that natural cytokines, predominantly IFN-gamma, produced by stimulated human intestinal lymphocytes and macrophages have the capacity to up-regulate dramatically pIgR expression in an intestinal epithelial cell line, strongly suggesting that their action in vivo leads to enhancement of local defense functions mediated by IgA.