IL-1β AND TNF-α, BUT NOT IFN-α, IFN-γ, IL-6 OR IL-8, ARE SECRETORY MEDIATORS IN HUMAN DISTAL COLON

Abstract

Inflammatory bowel disease (IBD) and HIV infection can cause diarrhoea which is accompanied by elevated cytokine levels. To elucidate a pathogenic role of cytokines, their effect on ion secretion was studied in human distal colon using the Ussing technique. Interluekin 1β (IL-1β) dose dependently increased short-circuit current (ISC). An ISCmaximum of 2.5±0.3 μmol.h−1.cm−2was reached at 20 ng/ml within 43±4 min.22Na+and36Cl−fluxes were not altered and residual flux increased by 2.4±1.0 μmol.h−1.cm−2indicating that the IL-1β-induced ISCis based on electrogenic bicarbonate secretion. IL-1β had no effect on HT-29/B6 epithlial monolayers suggesting that IL-1β does not act directly on the epithelium. Furthermore, in human colon the effect was not attenuated by removal of the submucosa (total stripping) pointing to a mediation step via subepithlial cells in the lamina propria. While tetrodotoxin and the 5-lipoxygenase inhibitor ICI-230487 had no effect, indomethacin completely blocked IL-1β action. Prostaglandin determination by RIA revealed an increased production of PGE2. At half maximum effective concentrations an additive action of tumour necrosis factor α (TNF-α) could be demonstrated on IL-1β-induced secretion. Interferon α (IFN-α), IFN-γ, IL-6, and IL-8 had no seretory effect in human distal colon. None of the investigated cytokines altered the intestinal barrier function. By their secretory effects IL-1β and TNF-α, but not IFN-α, IFN-γ, IL-6, and IL-8, may contribute to diarrhoea in IBD and AIDS.