Divergent effects of tumor necrosis factor-alpha and lymphotoxin-alpha on lethal endotoxemia and infection with live Salmonella typhimurium in mice

• Published in: European cytokine network (Montrouge) Vol. 13; no. 1; p. 104
• Main Authors: Dharmana, Edi, Keuter, Monique, Netea, Mihai G, Verschueren, Ineke C M M, Kullberg, Bart Jan
• Format: Journal Article
• Language: English
• Published: France 01.01.2002
• Subjects: Animals; Cytokines - biosynthesis; Cytokines - blood; Disease Susceptibility - physiopathology; Endotoxemia - chemically induced; Endotoxemia - mortality; Endotoxemia - physiopathology; Immunity, Innate - physiology; Lipopolysaccharides; Lymphotoxin-alpha - genetics; Lymphotoxin-alpha - physiology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Knockout; Neutrophils - cytology; Neutrophils - immunology; Phagocytosis - immunology; Phagocytosis - physiology; Salmonella Infections - mortality; Salmonella Infections - physiopathology; Salmonella typhimurium - pathogenicity; Survival Rate; Tumor Necrosis Factor-alpha - deficiency; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology
• ISSN: 1148-5493

During septic shock with Gram-negative microorganisms, mortality is determined by two independent factors: high concentrations of circulating proinflammatory cytokines and multiplication of the microorganisms in the organs of the host. We studied the role of endogenous tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha (LT) in the pathogenesis of lethal endotoxemia and infection with viable Salmonella typhimurium. Compared to wild-type control mice, TNF-/-LT-/- knock-out mice were more resistant (100% versus 25% mortality) to a lethal challenge with LPS, due to a significantly decreased production of the proinflammatory cytokines TNF, IL-1alpha and IL-1beta. In contrast, TNF-/-LT-/- mice were highly susceptible to infection with viable S. typhimurium as compared to wild-type mice (100% versus 0% mortality), and this was accompanied by a 100-fold greater bacterial load in their organs. The effect of endogenous TNF and LT during infection was mediated by a defective recruitment of neutrophils at the site of infection, as well as a reduced intracellular killing of S. typhimurium by these cells. These results show that TNF and LT have crucial, yet opposite effects on lethal endotoxemia induced by S. typhimurium LPS and on the infection of mice with live Salmonella microorganisms, and suggest caution when extrapolating results obtained in the lethal endotoxemia model to bacteremia in patients.