Inhibition of Na+,K+-ATPase by interferon gamma down-regulates intestinal epithelial transport and barrier function

Gastroenterology. 2001 May;120(6):1393-403. doi: 10.1053/gast.2001.24045.

Abstract

Background & aims: To determine how interferon (IFN)-gamma inhibits epithelial barrier and ion transport functions, intestinal T84 cells were studied.

Methods: Acute and chronic effects of IFN-gamma on T84 barrier function, Na+,K+-adenosine triphosphatase (ATPase) activity, and certain ion transport and tight junctional proteins were determined. To assess the role of Na+,K+-ATPase and intracellular Na+, similar studies with the Na+,K+-ATPase inhibitor ouabain and Na+ ionophore monensin were performed. To determine the role of nitric oxide (NO), the NO donor SPER-NO was used.

Results: IFN-gamma acutely (<6 hour) decreased cellular Na+,K+-ATPase activity, followed later (>24 hours) by decreases in expression of Na/K/2Cl, the alpha subunit of Na+,K+-ATPase, occludin, and ZO-1. In contrast, cystic fibrosis transmembrane conductance regulator or the Na+ pump beta subunit were unchanged. Ouabain and monensin caused nearly identical changes to IFN-gamma. Incubation in low Na+ media significantly blunted the chronic effects of IFN-gamma. Hypotonic-induced cell swelling, in contrast, had effects similar to IFN-gamma but did not alter the expression of the Na+ pump alpha subunit. The NO donor SPER-NO rapidly inhibited Na+,K+-ATPase and also down-regulated transport and barrier proteins.

Conclusions: IFN-gamma inhibition of Na+,K+-ATPase activity acutely causes increases in intracellular Na(i) concentration and cell volume, which are distinct signaling events that ultimately result in a leaky and dysfunctional epithelium associated with chronic inflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biological Transport / drug effects
  • Cell Line
  • Cell Size
  • Cell Survival / drug effects
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Interferon-gamma / pharmacology*
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Nitrogen Oxides
  • Ouabain / pharmacology
  • Sodium / metabolism
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*
  • Spermine / analogs & derivatives
  • Spermine / pharmacology

Substances

  • Enzyme Inhibitors
  • Nitrogen Oxides
  • spermine nitric oxide complex
  • Spermine
  • Ouabain
  • Interferon-gamma
  • Sodium
  • Sodium-Potassium-Exchanging ATPase