title: The diverse role of RIP kinases in necroptosis and inflammation.
abstract: Inflammation is a healthy response to infection or danger and should be rapid, specific and terminated once the threat has passed. Inflammatory diseases, where this regulation fails, cause considerable human suffering. Treatments have successfully targeted pro-inflammatory cytokines, such as tumor-necrosis factor (TNF), that directly induce genes encoding inflammatory products. Inflammatory signals, including TNF, may also directly induce caspase-independent cell death (necroptosis), which can also elicit inflammation. Necroptosis was originally defined as being dependent on the kinase RIPK1 but is now known to be dependent on RIPK3 and the pseudo-kinase MLKL. Therefore, RIPK1, RIPK3 and MLKL are potential therapeutic targets. RIPK1 and RIPK3 also directly regulate inflammatory signaling, which complicates interpretation of their function but might alter their therapeutic utility. This Review examines the role of cell death, particularly necroptosis, in inflammation, in the context of recent insights into the roles of the key necroptosis effector molecules RIPK1, RIPK3 and MLKL.
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: John
authors.identifier: 0000000276115774
authors.initials: J
authors.lastname: Silke
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Rickard
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Motti
authors.identifier: 0000000195181833
authors.initials: M
authors.lastname: Gerlic
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D018448:Models, Immunological; D009336:Necrosis / Q000276:immunology*; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D016207:Cytokines; C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases