RRC ID 15310
著者 Obata Y, Takahashi D, Ebisawa M, Kakiguchi K, Yonemura S, Jinnohara T, Kanaya T, Fujimura Y, Ohmae M, Hase K, Ohno H.
タイトル Epithelial cell-intrinsic Notch signaling plays an essential role in the maintenance of gut immune homeostasis.
ジャーナル J Immunol
Abstract Intestinal epithelial cells (IECs) have important functions as the first line of defense against diverse microorganisms on the luminal surface. Impaired integrity of IEC has been implicated in increasing the risk for inflammatory disorders in the gut. Notch signaling plays a critical role in the maintenance of epithelial integrity by regulating the balance of secretory and absorptive cell lineages, and also by facilitating epithelial cell proliferation. We show in this article that mice harboring IEC-specific deletion of Rbpj (RBP-J(ΔIEC)), a transcription factor that mediates signaling through Notch receptors, spontaneously develop chronic colitis characterized by the accumulation of Th17 cells in colonic lamina propria. Intestinal bacteria are responsible for the development of colitis, because their depletion with antibiotics prevented the development of colitis in RBP-J(ΔIEC) mice. Furthermore, bacterial translocation was evident in the colonic mucosa of RBP-J(ΔIEC) mice before the onset of colitis, suggesting attenuated epithelial barrier functions in these mice. Indeed, RBP-J(ΔIEC) mice displayed increase in intestinal permeability after rectal administration of FITC-dextran. In addition to the defect in physical barrier, loss of Notch signaling led to arrest of epithelial cell turnover caused by downregulation of Hes1, a transcriptional repressor of p27(Kip1) and p57(Kip2). Thus, epithelial cell-intrinsic Notch signaling ensures integrity and homeostasis of IEC, and this mechanism is required for containment of intestinal inflammation.
巻・号 188(5)
ページ 2427-36
公開日 2012-3-1
DOI 10.4049/jimmunol.1101128
PII jimmunol.1101128
PMID 22279105
MeSH Animals Bacterial Translocation / genetics Bacterial Translocation / immunology Cell Differentiation / genetics Cell Differentiation / immunology Chronic Disease Colitis / genetics Colitis / immunology Colitis / pathology Gene Deletion Homeostasis / genetics Homeostasis / immunology* Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics Intestinal Mucosa / immunology* Intestinal Mucosa / metabolism* Intestinal Mucosa / pathology Mice Mice, Knockout Mice, Transgenic Receptors, Notch / genetics Receptors, Notch / physiology* Signal Transduction / genetics Signal Transduction / immunology* Th17 Cells / immunology Th17 Cells / metabolism Th17 Cells / pathology
IF 4.886
引用数 39
WOS 分野 IMMUNOLOGY
リソース情報
実験動物マウス RBRC01071