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  • Review Article
  • Published:

TNF biology, pathogenic mechanisms and emerging therapeutic strategies

Key Points

  • TNF is a pleiotropic cytokine that exerts homeostatic and pathogenic bioactivities

  • A new concept in therapeutics of TNF-mediated diseases is the selective inhibition of the pathogenic effects of TNF with preservation of its homeostatic functions

  • TNF-induced necroptosis is a new pathway potentially implicated in TNF-mediated pathologies

  • TNF induces cellular priming, tolerization, and short-term transcriptional memory in a context-dependent manner

  • Combining TNF-blockade with drugs that target pathogenic pathways or cells not implicated in host defence is an attractive approach to improve effectiveness without compromising safety

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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Figure 1: Signalling modalities and bioactivities downstream of TNF receptors.
Figure 2: A model of TNFR–complex I signalling.
Figure 3: Molecular mechanisms of the differential induction kinetics of TNF-inducible genes.
Figure 4: TNF modulates cellular responses to subsequent challenges and imposes short-term memory.

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Acknowledgements

This work was supported by grants from the NIH (to L.B.I.) and the Feldstein Medical Foundation (to G.D.K.).

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Correspondence to Lionel B. Ivashkiv.

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Kalliolias, G., Ivashkiv, L. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12, 49–62 (2016). https://doi.org/10.1038/nrrheum.2015.169

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