Tumor necrosis factor-alpha induces Cl- and K+ secretion in human distal colon driven by prostaglandin E2

Am J Physiol. 1996 Oct;271(4 Pt 1):G669-74. doi: 10.1152/ajpgi.1996.271.4.G669.


Increased levels of tumor necrosis factor-alpha (TNF-alpha) have been found in, for example, inflammatory bowel disease (IBD) and human immunodeficiency virus (HIV) infection. 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 mumol.h-1.cm-2 was reached after 60 +/- 9 min at 200 ng/ml TNF-alpha. Bidirectional tracer flux measurements revealed that TNF-alpha induced an increase in 36 Cl serosal-to-mucosal flux, a decrease in 36Cl- mucosal-to-serosal 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) also had 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 toward 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport / drug effects
  • Cell Line
  • Chlorides / metabolism*
  • Colon / metabolism*
  • Cyclooxygenase Inhibitors / pharmacology
  • Diarrhea / physiopathology
  • Dinoprostone / physiology*
  • Eicosanoids / physiology
  • Humans
  • Indomethacin / pharmacology
  • Intestinal Mucosa / metabolism*
  • Potassium / metabolism*
  • Rubidium / metabolism
  • Sodium / metabolism
  • Tetrodotoxin / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Chlorides
  • Cyclooxygenase Inhibitors
  • Eicosanoids
  • Tumor Necrosis Factor-alpha
  • Tetrodotoxin
  • Sodium
  • Dinoprostone
  • Rubidium
  • Potassium
  • Indomethacin