| Title | RIP3 AND pMLKL promote necroptosis-induced inflammation and alter membrane permeability in intestinal epithelial cells |
|---|---|
| Publication Type | Articolo su Rivista peer-reviewed |
| Year of Publication | 2017 |
| Authors | Negroni, Anna, Colantoni Eleonora, Pierdomenico Maria, Palone Francesca, Costanzo Manuela, Oliva S., Tiberti A., Cucchiara S., and Stronati L. |
| Journal | Digestive and Liver Disease |
| Volume | 49 |
| Pagination | 1201-1210 |
| ISSN | 15908658 |
| Keywords | adolescent, alarmin, Amino Acid Chloromethyl Ketones, Apoptosis, article, azathioprine, benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone, beta actin, cadherin, Cadherins, Caspase 1, caspase 1p20, caspase 1p48, cell adhesion, Cell Membrane Permeability, cell migration, Cell Survival, Child, clinical article, colitis, controlled study, corticosteroid, Crohn disease, cryopyrin, drug effect, enteritis, enzyme activation, Epithelial Cells, epithelium cell, genetics, HCT 116 cell line, HCT116 Cells, high mobility group B1 protein, HMGB1 Protein, human, human cell, human tissue, Humans, imidazole derivative, Imidazoles, Immunoblotting, Immunofluorescence, immunohistochemistry, in vitro study, indole derivative, Indoles, inflammasome, Inflammasomes, inflammation, inflammatory bowel disease, interleukin 1beta, interleukin 1beta converting enzyme, interleukin 33, interleukin 8, Interleukin-1beta, Interleukin-8, Intestinal Mucosa, intestine biopsy, intestine epithelium cell, intestine mucosa, low drug dose, mesalazine, Messenger, messenger RNA, metabolism, methotrexate, mixed lineage kinase domain like protein, MLKL protein, necroptosis, Necrosis, necrostatin-1, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, NLR Family, NLRP3 protein, occludin, peptide chloromethyl ketone, Phosphorylation, physiology, Preschool, preschool child, priority journal, Protein, protein kinase, Protein Kinases, protein transport, Pyrin Domain-Containing 3 Protein, real time polymerase chain reaction, receptor interacting protein kinase 3, receptor interacting protein serine threonine kinase, Receptor-Interacting Protein Serine-Threonine Kinases, RIPK3 protein, RNA, transcription factor RelA, Tumor Necrosis Factor, Tumor Necrosis Factor-alpha, Ulcerative, ulcerative colitis, unclassified drug, uvomorulin, zonulin 1 |
| Abstract | Background Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). Aims The aim of this study is to examine in depth in vitro and ex vivo the contribution of necroptosis to intestinal inflammation. Methods In vitro: we used an intestinal cell line, HCT116RIP3, produced in our laboratory and overexpressing RIP3. Ex vivo: intestinal mucosal biopsies were taken from patients with inflammatory bowel disease (IBD) (20 with Crohn's disease; 20 with ulcerative colitis) and from 20 controls. Results RIP3-induced necroptosis triggers MLKL activation, increases cytokine/alarmin expression (IL-8, IL-1β, IL-33, HMGB1), NF-kBp65 translocation and NALP3 inflammasome assembly. It also affects membrane permeability by altering cell–cell junctional proteins (E-cadherin, Occludin, Zonulin-1). Targeting necroptosis through Necrostatin-1 significantly reduces intestinal inflammation in vitro and in cultured intestinal explants from IBD. Conclusion We show for the first time in vitro and ex vivo that RIP3-driven necroptosis seriously affects intestinal inflammation by increasing pMLKL, activating different cytokines and alarmins, and altering epithelial permeability. The inhibition of necroptosis causes a significant decrease of all these effects. These data strongly support the view that targeting necroptosis may represent a promising new option for the treatment of inflammatory enteropathies. © 2017 |
| Notes | cited By 0 |
| URL | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85028309015&doi=10.1016%2fj.dld.2017.08.017&partnerID=40&md5=59b369f944fff59dfe79a18e6c7a1929 |
| DOI | 10.1016/j.dld.2017.08.017 |
| Citation Key | Negroni20171201 |
