Tumor necrosis factor alpha regulates proliferation in a mouse intestinal cell line.
OBJECTIVE
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.
Kaiser
G C
GC
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2576, USA.
Polk
D B
DB
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003106:Colon / Q000166:cytology* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D007365:Intercellular Junctions / Q000502:physiology; D051379:Mice; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D000906:Antibodies; D006131:Growth Inhibitors; D006133:Growth Substances; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors