Acute-phase protein α1-antitrypsin--a novel regulator of angiopoietin-like protein 4 transcription and secretion

J Immunol. 2014 Jun 1;192(11):5354-62. doi: 10.4049/jimmunol.1400378. Epub 2014 Apr 23.

Abstract

The angiopoietin-like protein 4 (angptl4, also known as peroxisome proliferator-activated receptor [PPAR]γ-induced angiopoietin-related protein) is a multifunctional protein associated with acute-phase response. The mechanisms accounting for the increase in angptl4 expression are largely unknown. This study shows that human α1-antitrypsin (A1AT) upregulates expression and release of angplt4 in human blood adherent mononuclear cells and in primary human lung microvascular endothelial cells in a concentration- and time-dependent manner. Mononuclear cells treated for 1 h with A1AT (from 0.1 to 4 mg/ml) increased mRNA of angptl4 from 2- to 174-fold, respectively, relative to controls. In endothelial cells, the maximal effect on angptl4 expression was achieved at 8 h with 2 mg/ml A1AT (11-fold induction versus controls). In 10 emphysema patients receiving A1AT therapy (Prolastin), plasma angptl4 levels were higher relative to patients without therapy (nanograms per milliliter, mean [95% confidence interval] 127.1 [99.5-154.6] versus 76.8 [54.8-98.8], respectively, p = 0.045) and correlated with A1AT levels. The effect of A1AT on angptl4 expression was significantly diminished in cells pretreated with a specific inhibitor of ERK1/2 activation (UO126), irreversible and selective PPARγ antagonist (GW9662), or genistein, a ligand for PPARγ. GW9662 did not alter the ability of A1AT to induce ERK1/2 phosphorylation, suggesting that PPARγ is a critical mediator in the A1AT-driven angptl4 expression. In contrast, the forced accumulation of HIF-1α, an upregulator of angptl4 expression, enhanced the effect of A1AT. Thus, acute-phase protein A1AT is a physiological regulator of angptl4, another acute-phase protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-Like Protein 1
  • Angiopoietin-like Proteins
  • Angiopoietins / immunology*
  • Angiopoietins / metabolism
  • Anilides / pharmacology
  • Emphysema / drug therapy
  • Emphysema / immunology
  • Emphysema / pathology
  • Endothelial Cells / immunology*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology
  • Leukocytes, Mononuclear / immunology*
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / immunology
  • Male
  • Mitogen-Activated Protein Kinase 1 / immunology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / immunology
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphorylation / drug effects
  • Phosphorylation / immunology
  • Serine Proteinase Inhibitors / immunology
  • Serine Proteinase Inhibitors / pharmacology
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology*
  • alpha 1-Antitrypsin / immunology*
  • alpha 1-Antitrypsin / metabolism
  • alpha 1-Antitrypsin / pharmacology

Substances

  • 2-chloro-5-nitrobenzanilide
  • ANGPTL1 protein, human
  • Angiopoietin-Like Protein 1
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Anilides
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Serine Proteinase Inhibitors
  • Transcription Factors
  • alpha 1-Antitrypsin
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3