Systemic tumor necrosis factor-alpha production in experimental colitis

Abstract

Tumor necrosis factor-alpha (TNF) is a cytokine released by mononuclear cells in response to inflammation and sepsis. Since the biological effects of TNF are consistent with the systemic and nal features of ulcerative colitis, the role of TNF was examined in a rabbit model of chronic colitis. Peripheral blood mononuclear cells were isolated, stimulated with lipopolysaccharide, and cultured supernatants assayed for TNF levels using a cytotoxic assay on mouse fibrosarcoma L929 cells. Basal levels of TNF production by mononuclear cells from 13 normal rabbits (124.3 units/ml ± 27.1 units/ml, mean ± SE) were not different from nine rabbits with colitis (83.6 units/ml ± 24.4 units/ml, P > 0.05). Treatment with lipopolysaccharide (100 μg/ml) induced increased TNF production by mononuclear cells isolated from both normals (672.0 units/ml ± 197.5 units/ml, P < 0.05) and rabbits with colitis (1114.0 units/ml ± 489.6 units/ml, P < 0.05). However, at all lipopolysaccharide concentrations stimulated TNF levels were comparable in experimental and control groups (P > 0.05). In light of the role of leukotrienes in inflammation, a separate group of rabbits with colitis was investigated following treatment with an oral leukotriene B4 receptor antagonist. Serum TNF levels in 15 control rabbits (32.5 units/ml ± 7.6 units/ml, mean ± SE) were not significantly different from rabbits with colitis receiving either leukotriene B4 receptor antagonist (35.7 units/ml ± 9.2 units/ml, N = 13) or vehicle alone (50.3 units/ml ± 10.2 units/ml, N = 14) (ANOVA, P > 0.05). These data indicate that systemic levels of TNF are not elevated in this experimental model of chronic colitis. Therefore, other inflammatory mediators with biological functions parallel to those of TNF are likely to mediate the systemic manifestations of colitis.