The capacity for immune surveillance and protection against genetically alien agents is a basic property of multicellular organisms, and increasing significance in realizing this capacity is assigned to mech-anisms of innate immunity. The data accumulated to date show that many components of these mechanisms have a very wide spectrum of biological functions and play essential roles at different stages of ontogeny. An illustrative example is the signal system activated by tumor necrosis factor alpha (TNFα), which is responsible for the inflammation process. Analysis of its structural organization has shown that signaling mechanisms ini-tiating inflammation largely overlap with mechanisms of programmed cell death. This is why hypersecretion of TNFα may lead to systemic inflammatory reaction, or septic shock, and, hence, have a fatal outcome. Although studies on the TNFα-dependent mechanism have long history, many aspects of its regulation remain obscure. In particular, this concerns the nature of interspecific differences in the sensitivity of mam-mals to TNFα action and the ability of TNFα to activate oppositely directed cell programs depending on cell type or ambient conditions. The numerous data obtained in studies on different experimental systems need generalization and critical analysis. This review is an attempt at such an analysis. Its scope is concentrated on modern views on the divergence of TNFα-induced signal at the level of intracellular receptor-associated pro-teins. A description is given to potential “molecular triggers” responsible for switching between the main TNFα-dependent signaling pathways: inflammation, apoptosis, and necroptosis. The contribution of necroptosis (genetically programmed necrotic cell death) to the development of systemic inflammation and the lethal effect of TNFα are described. Consideration is also given to various lines of mice possessing natural resistance or sensitivity to TNFα, which hold much promise as models for deciphering the molecular genetic bases of the regulation of innate immune reactions and other TNFα-dependent processes.
Russian Journal of Developmental Biology – Springer Journals
Published: Jul 26, 2015
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