TNF and Lymphotoxin in host defense, autoimmunity and ca

Basic Sciences

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Abstract

We have characterized mice with TNF ablation in macrophages/neutrophils, T cells or B cells in several pathophysiological models. Macrophages and neutrophils are the main producers of serum TNF in models of septic shock and in acute liver toxicity. The same cell source of TNF is critical for protection against intracellular parasite, Listeria. Interestingly, TNF produced by T cells plays an important and non-redundant role in both host defense and in autoimmune liver injury induced by ConA. Ablation of either TNF, or LTa fails to modulate the frequency of spontaneous tumors in mice with p53 null background. However, deletion of the entire TNF/LT locus results in significant delay in tumor development in p53 null mice, suggesting the existence of a redundant pro-tumorigenic pathway controlled by one of TNF receptors. Finally, in collaboration with D. Mannel (University of Regensburg, Germany) we demonstrated that LT expressed by B cells can be used by tumors expressing LTbetaR to produce pro-angiogenic factors, required for tumor growth.