title: Anti-inflammatory Function of High-Density Lipoproteins via Autophagy of IκB Kinase.
abstract: OBJECTIVE
  Plasma levels of high-density lipoprotein (HDL) cholesterol are frequently found decreased in patients with inflammatory bowel disease (IBD). Therefore, and because HDL exerts anti-inflammatory activities, we investigated whether HDL and its major protein component apolipoprotein A-I (apoA-I) modulate mucosal inflammatory responses in vitro and in vivo.
  
  
  METHODS
  The human intestinal epithelial cell line T84 was used as the in vitro model for measuring the effects of HDL on the expression and secretion of tumor necrosis factor (TNF), interleukin-8 (IL-8), and intracellular adhesion molecule (ICAM). Nuclear factor-κB (NF-κB)-responsive promoter activity was studied by dual luciferase reporter assays. Mucosal damage from colitis induced by dextran sodium sulphate (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS) was scored by colonoscopy and histology in apoA-I transgenic (Tg) and apoA-I knockout (KO) and wild-type (WT) mice. Myeloperoxidase (MPO) activity and TNF and ICAM expression were determined in intestinal tissue samples. Autophagy was studied by Western blot analysis, immunofluorescence, and electron microscopy.
  
  
  RESULTS
  HDL and apoA-I down-regulated TNF-induced mRNA expression of TNF, IL-8, and ICAM, as well as TNF-induced NF-κB-responsive promoter activity. DSS/TNBS-treated apoA-I KO mice displayed increased mucosal damage upon both colonoscopy and histology, increased intestinal MPO activity and mRNA expression of TNF and ICAM as compared with WT and apoA-I Tg mice. In contrast, apoA-I Tg mice showed less severe symptoms monitored by colonoscopy and MPO activity in both the DSS and TNBS colitis models. In addition, HDL induced autophagy, leading to recruitment of phosphorylated IκB kinase to the autophagosome compartment, thereby preventing NF-κB activation and induction of cytokine expression.
  
  
  CONCLUSIONS
  Taken together, the in vitro and in vivo findings suggest that HDL and apoA-I suppress intestinal inflammation via autophagy and are potential therapeutic targets for the treatment of IBD.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Schlieren, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Ragam
authors.initials: R
authors.lastname: Gerster
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Schlieren, Switzerland.
authors.forename: Jyrki J
authors.initials: JJ
authors.lastname: Eloranta
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Hausmann
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Ruiz
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Cosin-Roger
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Terhalle
authors.affiliation: Centre for Microscopy and Image Analysis, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Ziegler
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Schlieren, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.affiliation: Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
keywords: 3-MA, 3-methyl adenine; ApoA-I, apolipoprotein A-I; Apolipoprotein A-I; Autophagy; CD, Crohn’s disease; DAPI, 4′,6-diamidino-2-phenylindole; DSS, dextran sodium sulphate; EMSA, electrophoretic mobility shift assay; HDL, high-density lipoprotein; IBD, inflammatory bowel disease; ICAM, intracellular adhesion molecule; IL, interleukin; Inflammatory Bowel Disease; KO, knockout; LC3II, light chain 3 II; MEICS, murine endoscopic index of colitis severity; MPO, myeloperoxidase; NF-κB; NF-κB, nuclear factor κB; PBS, phosphate-buffered saline; PFA, paraformaldehyde; PI-3, phosphatidylinositol-3; RT-PCR, real-time polymerase chain reaction; TNBS, 2,4,6-trinitrobenzenesulfonic acid; TNF, tumor necrosis factor; Tg, transgenic; WT, wild type; mTOR, the mammalian target of rapamycin; p-IKK, phosphorylated IκB kinase; siRNA, small interfering RNA