title: Crosstalk between TLR5 and Notch1 signaling in epithelial cells during intestinal inflammation.
abstract: During intestinal inflammation, a variety of signaling events are activated to perform several cell functions. Although the distinct roles of these pathways have been elucidated, the effects of their crosstalk activities remain to be clarified. We evaluated the crosstalk between two evolutionary conserved cell signaling systems, toll-like-receptor (TLR) 5 and Notch1, in intestinal epithelial cells during inflammation. Significant induction of the expression of Notch1 and Jagged1 was observed in the distal part of the colon, together with abundant localization of Notch1 intracellular domain (N1ICD) in the surface epithelium of inflamed colonic mucosa. By targeting intestinal epithelial cells, it was shown that recombination-signal-binding-protein-Jκ (RBP-Jκ)-mediated Notch functions are dependent on a flagellin-TLR5-mediated pathway. Conversely, using a γ-secretase inhibitor, we demonstrated that Notch synergistically increases TLR5‑mediated NF-κB activation. In addition, the effects of Notch on the NF-κB target gene interleukin-6 (IL-6) expression were revealed by evaluating the RBP-Jκ responsive element in the IL-6 promoter in vitro. Modulation of TLR5 and Notch crosstalk by transient blocking of Notch during the acute phase of colitis was beneficial for ameliorating colonic inflammation as well as disease status. In conclusion, the results suggest the effectiveness of Notch-targeted drug strategy for the treatment of intestinal inflammation.
authors.affiliation: Department of Internal Medicine II, Shimane University School of Medicine, Shimane 693-8051, Japan.
authors.forename: Monowar
authors.initials: M
authors.lastname: Aziz
authors.forename: Shunji
authors.initials: S
authors.lastname: Ishihara
authors.forename: Mesbah Uddin
authors.initials: MU
authors.lastname: Ansary
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sonoyama
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Tada
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oka
authors.forename: Ryusaku
authors.initials: R
authors.lastname: Kusunoki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tamagawa
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Fukuba
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mishima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mishiro
authors.forename: Naoki
authors.initials: N
authors.lastname: Oshima
authors.forename: Ichiro
authors.initials: I
authors.lastname: Moriyama
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishimura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yuki
authors.forename: Kousaku
authors.initials: K
authors.lastname: Kawashima
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kinoshita
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D051198:Toll-Like Receptor 5; D053829:Amyloid Precursor Protein Secretases