title: Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation.
abstract: OBJECTIVE
  Glucocorticoid-induced leucine zipper (GILZ) represents an anti-inflammatory mediator, whose downregulation has been described in various inflammatory processes. Aim of our study was to decipher the regulation of GILZ in vascular inflammation.
  
  
  RESULTS
  Degenerated aortocoronary saphenous vein bypass grafts (n = 15), which exhibited inflammatory cell activation as determined by enhanced monocyte chemoattractrant protein 1 (MCP-1, CCL2) and Toll-like receptor 2 (TLR2) expression, showed significantly diminished GILZ protein and mRNA levels compared to healthy veins (n = 23). GILZ was also downregulated in human umbilical vein endothelial cells (HUVEC) and macrophages upon treatment with the inflammatory cytokine TNF-α in a tristetraprolin (ZFP36, TTP)- and p38 MAPK-dependent manner. To assess the functional implications of decreased GILZ expression, we determined NF-κB activation after GILZ knockdown by siRNA and found that NF-κB activity and inflammatory gene expression were significantly enhanced. Importantly, ZFP36 is induced in TNF-α-activated HUVEC as well as in degenerated vein bypasses. When atheroprotective laminar shear stress was employed, GILZ levels in HUVEC increased on mRNA and protein level. Laminar flow also counteracted TNF-α-induced ZFP36 expression and GILZ downregulation. MAP kinase phosphatase 1 (MKP-1, DUSP1), a negative regulator of ZFP36 expression, was distinctly upregulated under laminar shear stress conditions and downregulated in degenerated vein bypasses.
  
  
  CONCLUSIONS
  Our data show a diminished expression of the anti-inflammatory mediator GILZ in the inflamed vasculature and indicate that GILZ downregulation requires the mRNA binding protein ZFP36. We suggest that reduced GILZ levels play a role in cardiovascular disease.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Hahn
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hoppstädter
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hirschfelder
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hachenthal
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Diesel
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Kessler
authors.affiliation: Department of Cardiothoracic Surgery, Völklingen Heart Centre, Völklingen, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Huwer
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany. Electronic address: pharm.bio.kiemer@mx.uni-saarland.de.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D001026:Coronary Artery Bypass / Q000009:adverse effects; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008264:Macrophages / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D012501:Saphenous Vein / Q000201:enzymology*; D015398:Signal Transduction; D013314:Stress, Mechanical; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051816:Tristetraprolin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014657:Vasculitis / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; C495342:TLR2 protein, human; C404226:TSC22D3 protein, human; D051195:Toll-Like Receptor 2; D014157:Transcription Factors; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Atherosclerosis; Laminar shear stress; NF-κB; Toll-like receptor 2 (TLR2); Tristetraprolin (TTP, ZFP36); Vein graft failure; mRNA stability