title: Roles of Toll-Like Receptor 4, IκB Kinase, and the Proteasome in the Intestinal Alterations Caused by Sepsis.
abstract: BACKGROUND
  Lipopolysaccharide decreases intestinal contractility and induces the production of cytokines, which play an important role in the pathogenesis of sepsis.
  
  
  OBJECTIVE
  The objective of the present study was to examine the role of Toll-like receptor 4, IκB kinase, and the proteasome in the intestinal alterations induced by lipopolysaccharide.
  
  
  METHODS
  Sepsis was induced in rabbits by intravenous injection of lipopolysaccharide. Contractility studies of rabbit duodenum were performed in an organ bath. Expressions of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, IκB kinase-α, IκB kinase-β, IκB kinase-γ, and the proteasome mRNA were determined by RT-PCR on rabbit duodenum.
  
  
  RESULTS
  Neomycin and polymyxin B (Toll-like receptor 4 inhibitors), IKK NBD peptide (IκB kinase complex inhibitor), and MG-132 (proteasome inhibitor) blocked partially the effects of lipopolysaccharide on the acetylcholine-, prostaglandin E2-, substance P-, and KCl-induced contractions in the longitudinal and circular smooth muscle of rabbit duodenum. Lipopolysaccharide increased the mRNA expression of interleukin-6 and interleukin-8 in duodenal tissue, and this effect was partly reversed by neomycin, polymyxin B, IKK NBD peptide, and MG-132. IκB kinase-α, IκB kinase-β, IκB kinase-γ, and the proteasome mRNA expressions was not affected by lipopolysaccharide treatment.
  
  
  CONCLUSIONS
  Toll-like receptor 4, the IκB kinase complex, and the proteasome could be therapeutic targets in the treatment of sepsis symptoms in the intestine.
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Veterinary Medicine, University of Zaragoza, c/ Miguel Servet 177, 50013, Saragossa, Spain, ser_pec@hotmail.com.
authors.forename: Sergio
authors.initials: S
authors.lastname: Gonzalo
authors.forename: Marta Sofía
authors.initials: MS
authors.lastname: Valero
authors.forename: Fernando
authors.initials: F
authors.lastname: Martínez de Salinas
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergara
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Arruebo
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Plaza
authors.forename: María Divina
authors.initials: MD
authors.lastname: Murillo
authors.forename: Laura
authors.initials: L
authors.lastname: Grasa
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D057846:Cell-Penetrating Peptides / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D004386:Duodenum / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004731:Endotoxins; D005769:Gastrointestinal Motility / Q000187:drug effects; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction; D009355:Neomycin / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D018805:Sepsis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction; D013373:Substance P / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D057846:Cell-Penetrating Peptides; D016207:Cytokines; D004731:Endotoxins; C575063:IKK NBD peptide; D018836:Inflammation Mediators; D007976:Leupeptins; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D051197:Toll-Like Receptor 4; D013373:Substance P; D011189:Potassium Chloride; C044101:endotoxin, Escherichia coli; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex; D009355:Neomycin; D011112:Polymyxin B; D015232:Dinoprostone; D000109:Acetylcholine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde