Using gene-deleted mice to evaluate the role of tumor necrosis factor and gamma-interferon in disease

Tumor necrosis factor (TNF) and interferon gamma (IFN$\gamma$) are important proinflammatory cytokines and have multiple roles in immune system development and function. The purpose of the present study was to investigate the individual or combined roles of TNF and IFN$\gamma$ in murine models of endotoxemia, asthma, and Pneumocystis carinii pneumonia using wild-type mice (WT) and mice deficient in TNF receptors 1 and 2 (TNFR1-2$\sp{{-}/{-}}$), IFN$\gamma$ (IFN$\gamma\sp{{-}/{-}}),$ and TNFR1, TNFR2, and IFN$\gamma$ (TNFR1-2-INF$\gamma\sp{{-}/{-}}).$ TNFR1-2-IFN$\gamma\sp{{-}/{-}}$mice were more resistant to intrapertioneally administered LPS and D-GalN/LPS as compared to WT, IFN$\gamma\sp{{-}/{-}},$ and TNFR1-2$\sp{{-}/{-}}$ mice. The resistance to LPS in TNFR1-2-IFN$\gamma\sp{{-}/{-}}$mice was associated with lower serum concentrations of IL-6. In contrast, compared to WT mice, IFN$\gamma\sp{{-}/{-}}$ and TNFR1-2$\sp{{-}/{-}}$ were not protected from LPS alone, and this lack of protection was associated with elevated serum concentrations of IFN$\gamma$ and IL-1 in TNFR1-2$\sp{{-}/{-}}$ mice and higher serum concentrations of TNF in IFN$\gamma\sp{{-}/{-}}$ mice. Thus, TNF and IFN$\gamma$ are synergistic protagonists in LPS-mediated lethality and blocking both cytokines significantly improves outcome in murine IP endotoxemia. In a model of asthma, TNFR1-2$\sp{{-}/{-}}$ mice and anti-murine TNF antibody treated WT mice did not have attenuated disease, but, instead had increased serum or lavage IgE levels. Additionally, compared to vehicle-only treated WT mice, WT mice treated chronically with mTNF had less severe pulmonary inflammation as characterized by lower numbers of bronchoalveolar eosinophils, decreased lung IL-4, and lower IL-5 concentrations in supernatants from stimulated lymph node cells. Taken together, TNF is not a critical protagonist in this murine model of asthma, and TNF may have important downregulatory effects in pulmonary inflammation. In a model of P. carinii infection, TNFR1-2-IFN$\gamma\sp{{-}/{-}}$ mice had marked pneumonia at 4 weeks. In contrast, WT, TNFR1-2$\sp{{-}/{-}}$ and IFN$\gamma\sp{{-}/{-}}$ mice cleared infection. Thus, TNF and IFN$\gamma$ are critical for a sufficient host response to P. carinii. The results from these three murine models demonstrate that TNF and IFN$\gamma$ gave diverse and synergistic roles in the immune response to disease. Furthermore, changing the bioactivity of TNF and INF$\gamma$ may be a rational approach for the treatment of a variety of diseases