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.
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.
Youngman
K R
KR
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106.
Fiocchi
C
C
Kaetzel
C S
CS
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D007422:Intestines / Q000166:cytology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis*; D051379:Mice; D011971:Receptors, Immunologic; D011994:Recombinant Proteins / Q000494:pharmacology; D012635:Secretory Component / Q000032:analysis*; D015854:Up-Regulation
D016207:Cytokines; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D012635:Secretory Component; D007371:Interferon-gamma