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α1-antitrypsin combines with plasma fatty acids and induces angiopoietin-like protein 4 expression

α1-Antitrypsin (A1AT) purified from human plasma upregulates expression and release of angiopoietin-like protein 4 (Angptl4) in adherent human blood monocytes and in human lung microvascular endothelial cells, providing a mechanism for the broad immune-regulatory properties of A1AT independent of it...

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Hauptverfasser: Frenzel, Eileen (VerfasserIn) , Wrenger, Sabine (VerfasserIn) , Brügger, Britta (VerfasserIn) , Salipalli, Sandeep (VerfasserIn) , Immenschuh, Stephan (VerfasserIn) , Aggarwal, Nupur (VerfasserIn) , Lichtinghagen, Ralf (VerfasserIn) , Mahadeva, Ravi (VerfasserIn) , Marcondes, A. Mario Q. (VerfasserIn) , Dinarello, Charles A. (VerfasserIn) , Welte, Tobias (VerfasserIn) , Janciauskiene, Sabina (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 11 September 2015
In: The journal of immunology
Year: 2015, Jahrgang: 195, Heft: 8, Pages: 3605-3616
ISSN:1550-6606
DOI:10.4049/jimmunol.1500740
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.4049/jimmunol.1500740
Verlag, lizenzpflichtig, Volltext: https://www.jimmunol.org/content/195/8/3605
Volltext
Verfasserangaben:Eileen Frenzel, Sabine Wrenger, Britta Brügger, Sandeep Salipalli, Stephan Immenschuh, Nupur Aggarwal, Ralf Lichtinghagen, Ravi Mahadeva, A. Mario Q. Marcondes, Charles A. Dinarello, Tobias Welte and Sabina Janciauskiene
Beschreibung
Zusammenfassung:α1-Antitrypsin (A1AT) purified from human plasma upregulates expression and release of angiopoietin-like protein 4 (Angptl4) in adherent human blood monocytes and in human lung microvascular endothelial cells, providing a mechanism for the broad immune-regulatory properties of A1AT independent of its antiprotease activity. In this study, we demonstrate that A1AT (Prolastin), a potent inducer of Angptl4, contains significant quantities of the fatty acids (FA) linoleic acid (C18:2) and oleic acid (C18:1). However, only trace amounts of FAs were present in preparations that failed to increase Angplt4 expression, for example, A1AT (Zemaira) or M-type A1AT purified by affinity chromatography. FA pull-down assays with Western blot analysis revealed a FA-binding ability of A1AT. In human blood-adherent monocytes, A1AT-FA conjugates upregulated expression of Angptl4 (54.9-fold, p < 0.001), FA-binding protein 4 (FABP4) (11.4-fold, p < 0.001), and, to a lesser degree, FA translocase (CD36) (3.1-fold, p < 0.001) relative to A1AT devoid of FA (A1AT-0). These latter effects of A1AT-FA were blocked by inhibitors of peroxisome proliferator-activated receptor (PPAR) β/δ (ST247) and PPARγ (GW9662). When compared with controls, cell pretreatment with ST247 diminished the effect of A1AT-LA on Angptl4 mRNA (11.6- versus 4.1-fold, p < 0.001) and FABP4 mRNA (5.4- versus 2.8-fold, p < 0.001). Similarly, preincubation of cells with GW9662 inhibited inducing effect of A1AT-LA on Angptl4 mRNA (by 2-fold, p < 0.001) and FABP4 mRNA (by 3-fold, p < 0.001). Thus, A1AT binds to FA, and it is this form of A1AT that induces Angptl4 and FABP4 expression via a PPAR-dependent pathway. These findings provide a mechanism for the unexplored area of A1AT biology independent of its antiprotease properties.
Beschreibung:Gesehen am 26.11.2020
Beschreibung:Online Resource
ISSN:1550-6606
DOI:10.4049/jimmunol.1500740

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