title: Involvement of interleukin-17A-induced hypercontractility of intestinal smooth muscle cells in persistent gut motor dysfunction.
abstract: OBJECTIVE
  The etiology of post-inflammatory gastrointestinal (GI) motility dysfunction, after resolution of acute symptoms of inflammatory bowel diseases (IBD) and intestinal infection, is largely unknown, however, a possible involvement of T cells is suggested.
  
  
  METHODS
  Using the mouse model of T cell activation-induced enteritis, we investigated whether enhancement of smooth muscle cell (SMC) contraction by interleukin (IL)-17A is involved in postinflammatory GI hypermotility.
  
  
  RESULTS
  Activation of CD3 induces temporal enteritis with GI hypomotility in the midst of, and hypermotility after resolution of, intestinal inflammation. Prolonged upregulation of IL-17A was prominent and IL-17A injection directly enhanced GI transit and contractility of intestinal strips. Postinflammatory hypermotility was not observed in IL-17A-deficient mice. Incubation of a muscle strip and SMCs with IL-17A in vitro resulted in enhanced contractility with increased phosphorylation of Ser19 in myosin light chain 2 (p-MLC), a surrogate marker as well as a critical mechanistic factor of SMC contractility. Using primary cultured murine and human intestinal SMCs, IκBζ- and p38 mitogen-activated protein kinase (p38MAPK)-mediated downregulation of the regulator of G protein signaling 4 (RGS4), which suppresses muscarinic signaling of contraction by promoting inactivation/desensitization of Gαq/11 protein, has been suggested to be involved in IL-17A-induced hypercontractility. The opposite effect of L-1β was mediated by IκBζ and c-jun N-terminal kinase (JNK) activation.
  
  
  CONCLUSIONS
  We propose and discuss the possible involvement of IL-17A and its downstream signaling cascade in SMCs in diarrheal hypermotility in various GI disorders.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Gastroenterology, Kitakyushu Municipal Medical Center, Fukuoka, Japan.
authors.forename: Hirotada
authors.initials: H
authors.lastname: Akiho
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Tokita
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
authors.forename: Mitsue
authors.initials: M
authors.lastname: Nishiyama
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsuchiya
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ohbuchi
authors.affiliation: Division of Laboratory Animal, Research Institute for Biomedical Science, Tokyo University of Science, Chiba, Japan; Core Research for Evolutional Science and Technology (CREST), JST, Saitama, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eikichi
authors.initials: E
authors.lastname: Ihara
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004751:Enteritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D005769:Gastrointestinal Motility; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C587672:IL1B protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D020710:RGS Proteins; C098799:RGS4 protein; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D009218:Myosins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11