Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1ß via CD36 and Nicotinic Acetylcholine Receptors.
Front Immunol
; 9: 877, 2018.
Article
in En
| MEDLINE
| ID: mdl-29922281
ABSTRACT
While interleukin (IL)-1ß 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-1ß secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1ß 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-1ß. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1ß 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-1ß from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1ß release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1ß 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 A2ß, 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-1ß 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alpha 1-Antitrypsin
/
Systemic Inflammatory Response Syndrome
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Interleukin-1beta
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Inflammasomes
Limits:
Animals
/
Humans
Language:
En
Journal:
Front Immunol
Year:
2018
Document type:
Article
Affiliation country: