Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency.

Autor:	Shouval DS; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Biswas A; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Kang YH; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Griffith AE; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Konnikova L; Harvard Medical School, Boston, MA, USA.; Divsion of Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Mascanfroni ID; Harvard Medical School, Boston, MA, USA.; Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital, Boston, MA, USA., Redhu NS; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Frei SM; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Field M; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Doty AL; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Immunology and Laboratory Medicine and, University of Florida, FL, USA., Goldsmith JD; Harvard Medical School, Boston, MA, USA.; Department of Pathology, Boston Children's Hospital, Boston, MA, USA., Bhan AK; Harvard Medical School, Boston, MA, USA.; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA., Loizides A; Division of Gastroenterology and Nutrition, The Children's Hospital at Montefiore, Bronx, NY, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Weiss B; Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Yerushalmi B; Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Yanagi T; Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Lui X; Department of Pathology, Immunology and Laboratory Medicine and, University of Florida, FL, USA., Quintana FJ; Harvard Medical School, Boston, MA, USA.; Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital, Boston, MA, USA., Muise AM; Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.; Institute of Medical Science, and Department of Biochemistry, University of Toronto, Toronto, ON, Canada.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Klein C; Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Horwitz BH; Harvard Medical School, Boston, MA, USA.; Department of Pathology Brigham and Women's Hospital, Boston, MA, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Glover SC; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Immunology and Laboratory Medicine and, University of Florida, FL, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Bousvaros A; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Snapper SB; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2016 Dec; Vol. 151 (6), pp. 1100-1104. Date of Electronic Publication: 2016 Sep 28.
DOI:	10.1053/j.gastro.2016.08.055
Abstrakt:	Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1β. We demonstrated that innate immune production of IL1β mediates colitis in IL10R-deficient mice. Transfer of Il1r1 -/- CD4 + T cells into Rag1 -/- /Il10rb -/- mice reduced the severity of their colitis (compared to mice that received CD4 + T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor-α, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1β through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb -/- mice or IL10R-deficient patients resulted in increased production of IL1β. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1β secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1-receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4-7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4 + T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency. (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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