Abstract
The clinical success of biologics that inhibit TNF (Tumor Necrosis Factor) in inflammatory bowel diseases (IBD), psoriasis and rheumatoid arthritis (RA) has clearly established a pathogenic role for this cytokine in these inflammatory disorders. TNF binding to its receptors activates NFκB and MAPK signaling, inducing the expression of downstream pro-inflammatory genes. This is thought to be the primary mechanism by which TNF elicits inflammation. TNF is also a well-known trigger of caspase-dependent apoptosis or caspase-independent necroptosis. Whether cell death has any role in TNF-mediated inflammation has been less clear. Emerging data from animal models now suggest that cellular demise caused by TNF may indeed provoke inflammation. The default response of most cells to TNF stimulation is survival, rather than death, due to the presence of two sequential cell death checkpoints. The early checkpoint is transcription-independent involving the non-degradative ubiquitination of RIPK1 to prevent RIPK1 from becoming a death-signaling molecule. The later checkpoint requires the induction of pro-survival genes by NFκB-mediated transcription. When the early checkpoint is disrupted, RIPK1 initiates cell death and we suggest the term ripoptocide to describe this manner of death (encompassing both apoptosis and necroptosis). The sensitivity of a cell to ripoptocide is determined by the balance between regulatory molecules that enforce and those that disassemble the early checkpoint. As there is evidence suggesting that ripoptocide is inflammatory, individuals may develop inflammation due to ripoptocide brought about by genetic, epigenetic or post-translational alteration of these checkpoint regulators. For these individuals, drugs that reinforce the early checkpoint and inhibit ripoptocide could be useful in ameliorating inflammation.
Highlights
Reviewed by: Najoua Lalaoui, Walter and Eliza Hall Institute of Medical Research, Australia Alexei Degterev, Tufts University, United States
When the early checkpoint is disrupted, RIPK1 initiates cell death and we suggest the term ripoptocide to describe this manner of death
We propose the term ripoptocide to describe cell death that is dependent on RIPK1, be it apoptosis or necroptosis
Summary
Tumor necrosis factor (TNF) was first described in 1975 as a serum factor that could lyse tumor cells present in bacillus Calmette-Guerin (BCG)-infected mice that were challenged with endotoxin (Carswell et al, 1975). Biologics that block TNF have proven to be highly effective in the treatment of these inflammatory disorders (Taylor and Feldmann, 2009; Blandizzi et al, 2014; Mitoma et al, 2018) This inflammatory role of TNF in both antimicrobial defense and in inflammatory disorders is thought to be due to its induction of NFκB and MAPK signaling, and subsequent transcription of downstream pro-inflammatory genes including other cytokines, chemokines, receptors and adhesion molecules. Another explanation for why TNF failed as an anti-tumor agent is that TNF is a poor inducer of tumor cell death when used as a single agent, contrary to its initial description as a cytotoxic factor. We will discuss our current understanding of the molecular mechanisms that determine whether a cell remains resistant or succumb to TNF-induced death and propose that tipping the response to death may be linked to inflammation in some patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
