TNF biology, pathogenic mechanisms and emerging therapeutic strategies

Abstract

TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of ‘short-term transcriptional memory’. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases.

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“…12 It is cytolytic to certain tumor cells. 13 It is an inducer of cytokines and cell adhesion molecules and is a regulator of proliferation/differentiation in lymphocytes and hemopoietic progenitors.…”

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“…Quang- Tam В то же время существуют данные, что IL-12 способствует стафилококковой колонизации [106] и препятствует благоприятному течению Staphylococcus aureus-индуцированного абсцес-са головного мозга [40], а назначение препаратов биологической терапии (в частности, устекину-маба), подавляющих активность IL-12, пациентам с неконтролируемым воспалением, вызванным Staphylococcus aureus, приводит к выздоровлению пациентов [49].…”