Acute-phase protein α1-antitrypsin--a novel regulator of angiopoietin-like protein 4 transcription and secretion.
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.
Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany;
Eileen
E
Frenzel
Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany;
Sabine
S
Wrenger
Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany;
Stephan
S
Immenschuh
Division of Pulmonary Diseases, Department of Internal Medicine, Philipps-Universität Marburg, 35037 Marburg, Germany;
Rembert
R
Koczulla
Department of Respiratory Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom;
Ravi
R
Mahadeva
Department of Medicine, University of Washington, Seattle, WA 98195; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and.
H Joachim
HJ
Deeg
Department of Medicine, University of Colorado Denver, Aurora, CO 80045.
Charles A
CA
Dinarello
Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany;
Tobias
T
Welte
Department of Medicine, University of Washington, Seattle, WA 98195; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and.
A Mario Q
AM
Marcondes
Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany; janciauskiene.sabina@mh-hannover.de.
Sabina
S
Janciauskiene
D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000276:immunology* / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D004646:Emphysema / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D015842:Serine Proteinase Inhibitors / Q000276:immunology / Q000494:pharmacology; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*; D000515:alpha 1-Antitrypsin / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; C117578:ANGPTL1 protein, human; D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000813:Anilides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D015842:Serine Proteinase Inhibitors; D014157:Transcription Factors; D000515:alpha 1-Antitrypsin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3