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RESEARCH PRODUCT
Anti-inflammatory Function of High-Density Lipoproteins via Autophagy of IκB Kinase
Jyrki J. ElorantaAnne TerhalleGerhard RoglerPedro A. RuizArnold Von EckardsteinJesus Cosin-rogerJesus Cosin-rogerRagam GersterUrs ZieglerMartin HausmannGerd A. Kullak-ublicksubject
WT wild typeApolipoprotein BEMSA electrophoretic mobility shift assayMPO myeloperoxidaseIκB kinaseDSS dextran sodium sulphatemTOR the mammalian target of rapamycinRT-PCR real-time polymerase chain reactionNF-κBchemistry.chemical_compound540 ChemistryApoA-I apolipoprotein A-I10038 Institute of Clinical ChemistryOriginal ResearchTNF tumor necrosis factorbiologyIBD inflammatory bowel diseaseChemistryGastroenterologyMyeloperoxidase10076 Center for Integrative Human PhysiologyMEICS murine endoscopic index of colitis severityTumor necrosis factor alphalipids (amino acids peptides and proteins)3-MA 3-methyl adenineNF-κB nuclear factor κBHDL high-density lipoproteinLC3II light chain 3 IIPBS phosphate-buffered salinep-IKK phosphorylated IκB kinase610 Medicine & healthICAM intracellular adhesion molecule246-Trinitrobenzenesulfonic acidTg transgenicmedicineAutophagyCD Crohn’s disease2715 GastroenterologyColitislcsh:RC799-869KO knockoutHepatologyApolipoprotein A-IAutophagyInflammatory Bowel DiseaseTNBS 246-trinitrobenzenesulfonic acidmedicine.diseaseMolecular biologyIL interleukinsiRNA small interfering RNAPI-3 phosphatidylinositol-3Immunologybiology.protein2721 Hepatologylcsh:Diseases of the digestive system. GastroenterologyPFA paraformaldehydeLipoproteinDAPI 4′6-diamidino-2-phenylindoledescription
Background & Aims: 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. Keywords: Apolipoprotein A-I, Autophagy, Inflammatory Bowel Disease, NF-κB
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-03-01 | CMGH Cellular and Molecular Gastroenterology and Hepatology |