title: Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling.
abstract: OBJECTIVE
  Few drugs have been found satisfactory in the treatment of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy. Toll-like receptor (TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan (LAM) or lipoteichoic acid (LTA), TLR2 agonists, attenuated indomethacin (IND)-induced intestinal damage.
  
  
  METHODS
  LAM (0.5 mg/kg) or LTA (15 mg/kg) was administered intraperitoneally to mice before IND (10 mg/kg) administration. Disease activity was evaluated macroscopically and histologically. In the migration analysis, fluorescence-labeled leukocyte movement in the intestinal microvessels was observed by intravital microscopy. Expression of P-selectin, MAdCAM-1, TLR2, TLR4, and F4/80 was observed immunohistochemically. In the in vitro analysis, RAW264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide (LPS), and the mRNA expression levels of TLR4, tumor necrosis factor-α, and interleukin-12p40 were measured.
  
  
  RESULTS
  Pretreatment with LAM or LTA significantly decreased IND-induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND-induced TLR4 expression on F4/80(+) macrophages, the level of P-selectin expression, and leukocyte migration in the small intestinal vessels. In the in vitro study, a single administration of LAM decreased TLR4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose-dependent manner.
  
  
  CONCLUSIONS
  TLR2 agonists attenuated IND-induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR4 signaling pathway in tissue macrophages.
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Kazuyuki
authors: K
authors: Narimatsu
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Masaaki
authors: M
authors: Higashiyama
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Chie
authors: C
authors: Kurihara
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Takeshi
authors: T
authors: Takajo
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Koji
authors: K
authors: Maruta
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Yuichi
authors: Y
authors: Yasutake
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Hirokazu
authors: H
authors: Sato
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Yoshikiyo
authors: Y
authors: Okada
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Chikako
authors: C
authors: Watanabe
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Shunsuke
authors: S
authors: Komoto
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Kengo
authors: K
authors: Tomita
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Shigeaki
authors: S
authors: Nagao
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Soichiro
authors: S
authors: Miura
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Ryota
authors: R
authors: Hokari
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D054441:Cell Migration Assays, Leukocyte; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D007079:Ileitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D007213:Indomethacin / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007962:Leukocytes / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013682:Teichoic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C050016:lipoarabinomannan; C009900:lipoteichoic acid; D007213:Indomethacin
keywords: Toll-like receptors; lipoarabinomannan; lipoteichoic acid; nonsteroidal anti-inflammatory agents