title: The epithelial danger signal IL-1α is a potent activator of fibroblasts and reactivator of intestinal inflammation.
abstract: Intestinal epithelial cell (IEC) death is typical of inflammatory bowel disease (IBD). We investigated: i) whether IEC-released necrotic cell products (proinflammatory mediators) amplify mucosal inflammation, ii) the capacity of necrotic cell lysates from HT29 cells or human IECs to induce human intestinal fibroblasts' (HIF) production of IL-6 and IL-8, and iii) whether IL-1α, released by injured colonocytes, exacerbated experimental IBD. Necrotic cell lysates potently induced HIF IL-6 and IL-8 production independent of Toll-like receptors 2 and 4, receptor for advanced glycation end-products, high-mobility group box 1, uric acid, IL-33, or inflammasome activation. IL-1α was the key IEC-derived necrotic cell product involved in HIF cytokine production. IL-1α-positive cells were identified in the epithelium in human IBD and dextran sulfate sodium (DSS)-induced colitis. IL-1α was detected in the stool of colitic mice before IL-1β. IL-1α enemas reactivated inflammation after DSS colitis recovery, induced IL-1 receptor expression in subepithelial fibroblasts, and activated de novo inflammation even in mice without overt colitis, after the administration of low-dose DSS. IL-1α amplifies gut inflammation by inducing cytokine production by mesenchymal cells. IL-1α-mediated IEC-fibroblast interaction may be involved in amplifying and perpetuating inflammation, even without obvious intestinal damage. IL-1α may be a target for treating early IBD or preventing the reactivation of IBD.
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio.
authors: Melania
authors: M
authors: Scarpa
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio.
authors: Sean
authors: S
authors: Kessler
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio.
authors: Tammy
authors: T
authors: Sadler
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio.
authors: Gail
authors: G
authors: West
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio.
authors: Craig
authors: C
authors: Homer
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors: Christine
authors: C
authors: McDonald
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio.
authors: Carol
authors: C
authors: de la Motte
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio.
authors: Claudio
authors: C
authors: Fiocchi
authors: Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio. Electronic address: styliae@ccf.org.
authors: Eleni
authors: E
authors: Stylianou
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D053582:Interleukin-1alpha / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D051379:Mice
chemical_list: D053582:Interleukin-1alpha; D015850:Interleukin-6; D016209:Interleukin-8; D016264:Dextran Sulfate