TY  - JOUR
A1  - Siebers, Kathrin
A1  - Fink, Bijan
A1  - Zakrzewicz, Anna
A1  - Agné, Alisa
A1  - Richter, Katrin
A1  - Konzok, Sebastian
A1  - Hecker, Andreas
A1  - Zukunft, Sven
A1  - Küllmar, Mira
A1  - Klein, Jochen
A1  - McIntosh, J. Michael
A1  - Timm, Thomas
A1  - Sewald, Katherina
A1  - Padberg, Winfried
A1  - Aggarwal, Nupur
A1  - Chamulitrat, Walee
A1  - Santoso, Sentot
A1  - Xia, Wendy
A1  - Janciauskiene, Sabina
A1  - Grau, Veronika
T1  - Alpha-1 Antitrypsin inhibits ATP-mediated release of Interleukin-1β via CD36 and Nicotinic Acetylcholine receptors
T2  - Frontiers in immunology
N2  - While interleukin (IL)-1β 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-1β 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-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT 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 AAT controls ATP-induced IL-1β 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.
KW  - CD36
KW  - CHRNA7
KW  - CHRNA9
KW  - CHRNA10
KW  - inflammasome
KW  - interleukin-1β
KW  - calcium-independent phospholipase A2β
KW  - P2X7 receptor
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46868
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-468681
SN  - 1664-3224
N1  - Copyright: © 2018 Siebers, Fink, Zakrzewicz, Agné, Richter, Konzok, Hecker, Zukunft, Küllmar, Klein, McIntosh, Timm, Sewald, Padberg, Aggarwal, Chamulitrat, Santoso, Xia, Janciauskiene and Grau. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
VL  - 9
IS  - Art. 877
SP  - 1
EP  - 15
PB  - Frontiers Media
CY  - Lausanne
ER  -