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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. (Gastroenterology 1997 Apr;112(4):1231-40)