Tumor necrosis factor alpha induces cl- and k+ secretion in human
distal colon driven by prostaglandin e2.
Schmitz, H., M. Fromm, H. Bode, P. Scholz, E. O. Riecken, and J. D.
Schulzke.
Departments of Gastroenterology and Clinical Physiology,
Universit[umlaut]atsklinikum Benjamin Franklin, Freie
Universit[umlaut]at Berlin, D-12200 Berlin, Germany, Schering AG,
M[umlaut]ullerstr. 178, D-13353 Berlin, Germany
APStracts 3:0084G, 1996.
Increased levels of tumor necrosis factor alpha (TNF[alpha]) have been
found e.g. in inflammatory bowel disease (IBD) and HIV infection. In
order to investigate a possible contribution of TNF[alpha] to the
pathogenesis of diarrhea in these diseases, ion transport of human
distal colon was studied in the Ussing-chamber in vitro. Serosal
addition of TNF[alpha] increased short circuit current (ISC) of
partially stripped tissues in a dose-dependent manner. Maximum ISC
increase of 1.8+/-0.2 [mu]mol x h-1 x cm-2 was reached after 60+/-9
min at 200 ng/ml TNF[alpha]. Bi-directional tracer flux measurements
revealed that TNF[alpha] induced an increase in 36Cl- s-to-m flux, a
decrease in 36Cl- m-to-s flux, and a slight increase in K+ secretion
indicated by an increased secretory 86Rb net flux. In the highly
differentiated colonic epithelial cell line HT-29/B6 TNF[alpha] had
no effect on ISC, suggesting a mediation step located in the
subepithelium. This supposition was supported by measurements on
totally stripped human tissues, since removal of subepithelial layers
by total stripping reduced the TNF[alpha] effect by 40%. Experiments
with tetrodotoxin (10-6 M) indicated that the TNF[alpha] effect was
not mediated by the enteric nervous system. The specific 5
-lipoxygenase blocker ICI 230487 (5 x 10-8 M) had also no effect on
TNF[alpha] action. In contrast, inhibition of cyclooxygenase by
indomethacin (10-6 M) inhibited the effect of TNF[alpha].
Radioimmunoassay of prostaglandin E2 (PGE2) in the serosal bathing
solution revealed an increase in PGE2 production/release after
addition of TNF[alpha], which paralleled the ISC response. We
conclude that TNF[alpha] changed Cl- and K+ transport towards
secretion in human colon. This effect was mediated by PGE2 produced
by subepithelial cells. Thus, TNF[alpha] could be a mediator of
diarrhea during intestinal inflammation, e.g. in IBD and HIV
infection.
Received 26 February 1996; accepted in final form 2 April 1996.
APS Manuscript Number G76-6.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 23 April 96