title: Activation of TGF-βactivated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease.
abstract: The etiology and mechanisms for inflammatory bowel disease (IBD) are incompletely known. Determination of new, clinically important mechanisms for intestinal inflammation is imperative for developing effective therapies to treat IBD We sought to define a widespread mechanism for colon mucosal inflammation via the activation of TGF-βactivated Kinase 1 (TAK1), a central regulator of cellular inflammatory actions. Activation of TAK1 and the downstream inflammatory signaling mediators was determined in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD) as well as in DSS-induced and spontaneous IBD in mice. The role of TAK1 in facilitating intestinal inflammation in murine models of IBD was investigated by using (5Z)-7-Oxozeaenol, a highly selective pharmacological inhibitor of TAK1. We found hyper-activation of TAK1 in patients with UC or CD and in murine models of IBD Pharmacological inhibition of TAK1 prevented loss in body weight, disease activity, microscopic histopathology, infiltration of inflammatory cells in the colon mucosa, and elevated proinflammatory cytokine production in two murine models of IBD We demonstrated that at the early phase of the disease activation of TAK1 is restricted in the epithelial cells. However, at a more advanced stage of the disease, TAK1 activation predominantly occurs in nonepithelial cells, especially in macrophages. These findings elucidate the activation of TAK1 as crucial in promoting intestinal inflammation. Thus, the TAK1 activation pathway may represent a suitable target to design new therapies for treating IBD in humans.
authors.affiliation: Department of Pediatrics, Center for Prevention of Preterm Birth Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati Ohio.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Center for Prevention of Preterm Birth Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati Ohio.
authors.forename: Fansheng
authors.initials: F
authors.lastname: Kong
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Jefferson E
authors.initials: JE
authors.lastname: Vallance
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Eleana
authors.initials: E
authors.lastname: Harmel-Laws
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Surya
authors.initials: S
authors.lastname: Amarachintha
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Kris A
authors.initials: KA
authors.lastname: Steinbrecher
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.affiliation: Department of Pediatrics, Center for Prevention of Preterm Birth Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati Ohio Sandip.Bhattacharyya@cchmc.org.
authors.forename: Sandip
authors.initials: S
authors.lastname: Bhattacharyya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C556062:IL10 protein, mouse; C481053:TAB3 protein, human; D016753:Interleukin-10
keywords: Glucocorticoid; TAK1; intestinal inflammation