Necrosis-dependent and independent signaling of the RIP kinases in inflammation |
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| Institution: | 1. Swiss HPB (Hepato-Pancreato-Biliary) Center, University Hospital Zürich, Switzerland;2. Institute for Virology, Helmholtz-Zentrum München, Germany;3. Institute for Virology, Technische Universität München, Germany;1. Joint Center for Translational Research of Chronic Diseases, Changhai Hospital, The Second Military Medical University, Shanghai 2000433, China;2. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, NY 10021, USA;3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA;4. Program in Cellular and Molecular Medicine, Boston Children''s Hospital, Boston, MA 02115, USA;5. Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA;1. AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, United States;2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082, United States;1. Committee on Immunology, University of Chicago, United States;2. Department of Pathology, University of Chicago, United States;1. Department of Microbiology, The University of Iowa, USA;2. The Graduate Program in Immunology, The University of Iowa, USA;3. Department of Internal Medicine, The University of Iowa, USA;4. Veterans Affairs Medical Center, Iowa City, IA 52242, USA |
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| Abstract: | It is now widely accepted that some forms of necrosis are controlled by a dedicated signaling pathway triggered by various cell surface and intracellular receptors. This regulated form of necrosis is mediated by the kinase activity of receptor-interacting protein kinase 1 (RIP1/RIPK1) and/or RIP3/RIPK3. A number of studies using the RIP1 kinase inhibitor Necrostatin-1 (Nec-1) and its derivatives, or RIP3-deficient mice demonstrated that RIP1 and RIP3 are involved in various infectious and sterile inflammatory diseases. As a consequence, these specific phenotypes were construed to depend on necrosis. However, emerging evidence indicates that the RIP1 kinase activity and RIP3 can also control apoptosis and inflammatory cytokine production independent of necrosis. Therefore, we may need to re-interpret conclusions drawn based on loss of RIP1 or RIP3 functions in in vivo models. We propose that studies of RIP1 and RIP3 in different inflammatory responses need to consider cell death-dependent and independent mechanisms of the RIP kinases. |
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| Keywords: | NF-κB Inflammasome TNF Caspase 8 Fadd MLKL |
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