title: Regulation and function of bone morphogenetic protein signaling in colonic injury and inflammation.
abstract: The bone morphogenetic proteins (BMPs) regulate gastrointestinal homeostasis. We investigated the expression of BMP-4 and the localization and function of BMP signaling during colonic injury and inflammation. Mice expressing the β-galactosidase (β-gal) gene under the control of a BMP-responsive element (BRE), BMP-4-β-gal/ mice, and animals generated by crossing villin-Cre mice to mice with floxed alleles of BMP receptor 1A (villin-Cre;Bmpr1aflox/flox) were treated with dextran sodium sulfate (DSS) to induce colonic injury and inflammation. Expression of BMP-4, β-gal, BMPR1A, IL-8, α-smooth muscle actin, and phosphorylated Smad1, -5, and -8 was assessed by X-Gal staining, quantitative RT-PCR, and immunohistochemistry. Morphology of the colonic mucosa was examined by staining with hematoxylin and eosin. The effect of IFN-γ, TNF-α, IL-1β, and IL-6 on BMP-4 mRNA expression was investigated in human intestinal fibroblasts, whereas that of BMP-4 on IL-8 was assessed in human colonic organoids. BMP-4 was localized in α-smooth muscle actin-positive mesenchymal cells while the majority of BMP-generated signals targeted the epithelium. DSS caused injury and inflammation leading to reduced expression of BMP-4 and of BMPR1A mRNAs, and to decreased BMP signaling. Deletion of BMPR1A enhanced colonic inflammation and damage. Administration of anti-TNF-α antibodies to DSS-treated mice ameliorated colonic inflammation and increased the expression of BMP-4 and BMPR1A mRNAs. TNF-α and IL-1β inhibited both basal and IFN-γ-stimulated BMP-4 expression, whereas IL-6 had no effect. BMP-4 reduced TNF-α-stimulated IL-8 mRNA expressor IL-8 mRNA expression in the organoids. Inflammation and injury inhibit BMP-4 expression and signaling, leading to enhanced colonic damage and inflammation. These observations underscore the importance of BMP signaling in the regulation of intestinal inflammation and homeostasis.
  
  
  
  In this study we report a series of novel observations that underscore the importance of bone morphogenetic protein (BMP) signaling in the regulation of colonic homeostasis during the development of injury and inflammation. In particular, we present evidence that BMP signaling mitigates the response of the colonic epithelium to injury and inflammation and that cytokines, such as TNF-α and IL-1β, inhibit the expression of BMP-4.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Tuo
authors.initials: T
authors.lastname: Ji
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Takabayashi
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Maria
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan; and.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Brazil
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Eaton
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan; atodisco@umich.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Todisco
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D016898:Interferon-alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha
keywords: bone morphogenetic protein-responsive element; chemokines; cytokines; myofibroblasts