Journalartikel

Jahr der Veröffentlichung: 2018

Zeitschrift: Frontiers in Immunology

Bandnummer: 9

ISSN: 1664-3224

Open Access Status: Gold

DOI Link: https://doi.org/10.3389/fimmu.2018.00877

Verlag: Frontiers Media

Abstract: 
While interleukin (IL)-1 beta 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-1 beta secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1 beta 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-1 beta. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1 beta 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-1 beta from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1 beta release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1 beta 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 A2 beta, 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-1 beta 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.

Harvard-Zitierstil: Siebers, K., Fink, B., Zakrzewicz, A., Agne, A., Richter, K., Konzok, S., et al. (2018) Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1β via CD36 and Nicotinic Acetylcholine Receptors, Frontiers in Immunology, 9, Article 877. https://doi.org/10.3389/fimmu.2018.00877

APA-Zitierstil: Siebers, K., Fink, B., Zakrzewicz, A., Agne, A., Richter, K., Konzok, S., Hecker, A., Zukunft, S., Küllmar, M., Klein, J., McIntosh, J., Timm, T., Sewald, K., Padberg, W., Aggarwal, N., Chamulitrat, W., Santoso, S., Xia, W., Janciauskiene, S., ...Grau, V. (2018). Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1β via CD36 and Nicotinic Acetylcholine Receptors. Frontiers in Immunology. 9, Article 877. https://doi.org/10.3389/fimmu.2018.00877