IL-1-BETA AND TNF-ALPHA, BUT NOT IFN-ALPHA, IFN-GAMMA, IL-6 OR IL-8, ARE SECRETORY MEDIATORS IN HUMAN DISTAL COLON

Inflammatory bowel disease (IBD) and HIV infection can cause diarrhoea which are accompanied by elevated cytokine levels, To elucidate a pat hogenic role of cytokines, their effect on ion secretion was studied i n human distal colon using the Ussing technique. Interleukin 1 beta (I L-1 beta) dose dependently increased short-circuit current (I-SC) An I -SC maximum of 2.5 +/- 0.3 mu mol.h(-1).cm(-2) was reached at 20 ng/ml within 43 +/- 4 min. Na-22(+) and Cl-36(-) fluxes were not altered an d residual flux increased by 2.4 +/- 1.0 mu mol.h(-1).cm(2) indicating that the IL-l beta-induced I-SC is based on electrogenic bicarbonate secretion. IL-1 beta had no effect on HT-29/B6 epithelial monolayers s uggesting that IL-1 beta does not act directly on the epithelium. Furt hermore, in human colon the effect was not attenuated by removal of th e submucosa (total stripping) pointing to a mediation step via subepit helial cells in the lamina propria, While tetrodotoxin and the 5-lipox ygenase inhibitor ICI-230487 had no effect, indomethacin completely bl ocked IL-1 beta action. Prostaglandin determination by RIA revealed an increased production of PGE(2), At half maximum effective concentrati ons an additive action of tumour necrosis factor alpha (TNF-alpha) cou ld be demonstrated on IL-1 beta-induced secretion. Interferon alpha (I FN-alpha), IFN-gamma, IL-6, and IL-8 had no secretory effect in human distal colon. None of the investigated cytokines altered the intestina l barrier function. By their secretory effects IL-1 beta and TNF-alpha , but not IFN-alpha, IFN-gamma, IL-6, and IL-8, may contribute to diar rhoea in IBD and AIDS. (C) 1998 Academic Press Limited.