Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NF-kappa B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli

Peter A Henriksen, Mary Hitt, Zhou Xing, Jun Wang, Chris Haslett, Rudolph A Riemersma, David J Webb, Yuri V Kotelevtsev, Jean-Michel Sallenave

Research output: Contribution to journalArticlepeer-review

Abstract

Atherosclerosis is a chronic inflammatory disease affecting arterial vessels. Strategies to reduce the inflammatory responses of endothelial cells and macrophages may slow lesion development and prevent complications such as plaque rupture. The human protease human neutrophil elastase (HNE), oxidized low density lipoprotein, LPS, and TNF-alpha were chosen as model stimuli of arterial wall inflammation and led to production of the chemokine IL-8 in endothelial cells. To counteract the activity of HNE, we have examined the effects of adenoviral gene delivery of the anti-elastases elafin, previously demonstrated within human atheroma, and murine secretory leukocyte protease inhibitor (SLPI), a related molecule, on the inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. We developed a technique of precomplexing adenovirus with cationic lipid to augment adenoviral infection efficiency in endothelial cells and to facilitate infection in macrophages. Elafin overexpression protected endothelial cells from HNE-induced IL-8 production and cytotoxicity. Elafin and murine SLPI also reduced endothelial IL-8 release in response to oxidized low density lipoprotein, LPS, and TNF-alpha and macrophage TNF-alpha production in response to LPS. This effect was associated with reduced activation of the inflammatory transcription factor NF-kappaB, through up-regulation of IkappaBalpha, in both cell types. Our work suggests a novel and extended anti-inflammatory role for these HNE inhibitors working as effectors of innate immunity to protect tissues against maladaptive inflammatory responses. Our findings indicate that elafin and SLPI may be gene therapy targets for the treatment of atheroma.

Original languageEnglish
Pages (from-to)4535-44
Number of pages10
JournalJournal of Immunology
Volume172
Issue number7
Publication statusPublished - 1 Apr 2004

Keywords

  • Adenoviridae/genetics
  • Animals
  • Arteriosclerosis/enzymology
  • Cations
  • Cell Line
  • Cytokines/antagonists & inhibitors
  • Endothelium, Vascular/immunology
  • Humans
  • I-kappa B Proteins/antagonists & inhibitors
  • Interleukin-8/biosynthesis
  • Leukocyte Elastase/antagonists & inhibitors
  • Lipopolysaccharides/pharmacology
  • Lipoproteins, LDL/pharmacology
  • Liposomes
  • Lung/immunology
  • Macrophages/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • NF-KappaB Inhibitor alpha
  • NF-kappa B/antagonists & inhibitors
  • Proteinase Inhibitory Proteins, Secretory
  • Proteins/genetics
  • Respiratory Mucosa/immunology
  • Secretory Leukocyte Peptidase Inhibitor
  • Transfection/methods
  • Tumor Necrosis Factor-alpha/pharmacology
  • Up-Regulation/immunology

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