Alpha-1-antitrypsin binds to the glucocorticoid receptor with anti-inflammatory and anti-mycobacterial significance in macrophages
Alpha-1-antitrypsin (AAT), a serine protease inhibitor, is the third most abundant protein in plasma. While the best-known function of AAT is irreversible inhibition of elastase, AAT is an acute-phase reactant and is increasingly recognized to have a panoply of other functions including as an anti-i...
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Published in | The Journal of immunology (1950) Vol. 209; no. 9; pp. 1746 - 1759 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
26.09.2022
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Online Access | Get full text |
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Summary: | Alpha-1-antitrypsin (AAT), a serine protease inhibitor, is the third most abundant protein in plasma. While the best-known function of AAT is irreversible inhibition of elastase, AAT is an acute-phase reactant and is increasingly recognized to have a panoply of other functions including as an anti-inflammatory mediator and a host-protective molecule against various pathogens. While a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Since AAT has anti-inflammatory properties, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in human macrophages. We report the novel finding that AAT binds to GR using several approaches, including co-immunoprecipitation, mass spectrometry, and microscale thermophoresis. We also performed
in silico
molecular modeling and found that binding between AAT and GR has a plausible stereochemical basis. The significance of this interaction in macrophages is evinced by AAT inhibition of lipopolysaccharide-induced nuclear factor-kappa B activation and interleukin-8 production as well as AAT induction of angiopoietin-like-4 protein are, in part, dependent on GR. Furthermore, this AAT–GR interaction contributes to a host-protective role against mycobacteria in macrophages. In summary, this study identifies a new mechanism for the gene regulation, anti-inflammatory, and host-defense properties of AAT. |
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ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.2200227 |