Tumor necrosis factor alpha regulates proliferation in a mouse intestinal cell line

Gastroenterology. 1997 Apr;112(4):1231-40. doi: 10.1016/s0016-5085(97)70135-5.


Background & aims: Tumor necrosis factor (TNF)-alpha is a prominent cytokine in the pathogenesis of inflammatory bowel disease, yet its effects on the intestinal epithelium remain poorly understood. This study was designed to investigate the action of TNF-alpha on intestinal cell proliferation.

Methods: Young adult mouse colon cells were studied under nontransformed conditions with epidermal growth factor, keratinocyte growth factor, insulin-like growth factor 1, or serum in the presence or absence of TNF-alpha and cell numbers determined. The expression and independent actions of the 55-kilodalton TNF-alpha R1 and 75-kilodalton TNF-alpha R2 receptors were studied by immunologic methods.

Results: TNF-alpha stimulated proliferation at 0.1 and 1 ng/mL and inhibited proliferation at 100 and 1000 ng/mL without altering cell viability. TNF-alpha inhibited the mitogenic effect of growth factors and epidermal growth factor receptor tyrosine phosphorylation. TNF-alpha R1 receptor agonist antibody inhibited proliferation, whereas a TNF-alpha R2 receptor-blocking antibody prevented the proliferative effect of low-dose TNF-alpha.

Conclusions: TNF-alpha displays a novel influence on intestinal cell growth, stimulating proliferation at physiological concentrations and inhibiting proliferation at pathological concentrations. The regulation of intestinal cell mitogenesis by TNF-alpha seems to be mediated differentially by the two TNF-alpha receptors, with the TNF-alpha R1 receptor inhibiting proliferation and the TNF-alpha R2 receptor promoting proliferation.

Publication types

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

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Cell Count / drug effects
  • Cell Division / drug effects
  • Cell Line
  • Colon / cytology*
  • Colon / drug effects
  • Dose-Response Relationship, Drug
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Growth Inhibitors / pharmacology
  • Growth Substances / pharmacology
  • Intercellular Junctions / physiology
  • Mice
  • Osmolar Concentration
  • Phosphorylation / drug effects
  • Receptors, Tumor Necrosis Factor / agonists
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tyrosine / metabolism


  • Antibodies
  • Growth Inhibitors
  • Growth Substances
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Tyrosine
  • Epidermal Growth Factor
  • ErbB Receptors