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Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1beta via CD36 and Nicotinic Acetylcholine Receptors

Siebers, Kathrin ; Fink, Bijan ; Zakrzewicz, Anna ; Agne, Alisa ; Richter, Katrin ; Konzok, Sebastian ; Hecker, Andreas ; Zukunft, Sven ; Küllmar, Mira ; Klein, Jochen ; McIntosh, J. Michael ; Timm, Thomas ; Sewald, Katherina ; Padberg, Winfried ; Aggarwal, Nupur ; Chamulitrat, Walee ; Santoso, Sentot ; Xia, Wendy ; Janciauskiene, Sabina ; Grau, Veronika


Originalveröffentlichung: (2018) Frontiers in Immunology 9(877) doi: 10.3389/fimmu.2018.00877
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URN: urn:nbn:de:hebis:26-opus-146306
URL: http://geb.uni-giessen.de/geb/volltexte/2019/14630/

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Freie Schlagwörter (Englisch): CD36 , CHRNA7 , CHRNA9 , CHRNA10 , inflammasome
Sammlung: Open Access - Publikationsfonds
Universität Justus-Liebig-Universität Gießen
Institut: Department of General and Thoracic Surgery
Fachgebiet: Medizin
DDC-Sachgruppe: Medizin
Dokumentart: Aufsatz
Sprache: Englisch
Erstellungsjahr: 2018
Publikationsdatum: 20.05.2019
Kurzfassung auf Englisch: While interleukin (IL)-1beta is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1beta secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1beta. The human anti-protease alpha-1 antitrypsin and IL-1beta regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of alpha-1 antitrypsin efficiently inhibit ATP-induced release of IL-1beta from primary human blood mononuclear cells, monocytic U937 cells and rat lung tissue, whereas ATP-independent IL-1beta release is not impaired. Both, native and oxidized alpha-1 antitrypsin are active, suggesting that the inhibition of IL-1beta release is independent of the anti-elastase activity of alpha-1 antitrypsin. Signaling of alpha-1 antitrypsin in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that alpha-1 antitrypsin controls ATP-induced IL-1beta release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
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