Universität zu Köln

Sarabhai, Theresia, Peter, Christoph, Baer, Anne-Kathrin, Windolf, Joachim, Relja, Borna ORCID: 0000-0002-5625-8823, Wesselborg, Sebastian ORCID: 0000-0002-5236-942X, Wahlers, Thorsten and Paunel-Goerguelue, Adnana (2017). Serum alpha-1 Antitrypsin (AAT) antagonizes intrinsic apoptosis induction in neutrophils from patients with systemic inflammatory response syndrome. PLoS One, 12 (5). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein alpha-1 Antitrypsin (AAT) as a potent suppressor of stauros-porine (STS)-induced apoptosis in human neutrophils through a mechanism implicating cas-pases-independent pathways. We show here that serum levels of AAT, potentially in part released by stimulated neutrophils, are markedly elevated in major trauma patients suffering from systemic inflammatory response syndrome (SIRS). Notably, AAT depletion from serum increased sensitivity of human neutrophils for STS-induced cell death. In fact, AAT was demonstrated to confer intrinsic apoptosis resistance by preventing PKC/Akt inactivation and subsequent proteasomal degradation of antiapoptotic Mcl-1 protein in response to STS treatment. Neither MAP kinase ERK1/2 nor caspases were found to be involved in AAT-triggered antiapoptotic pathways in neutrophils. In summary, these results establish a novel pivotal role of circulating AAT in mediating survival by antagonizing the proapoptotic action of the PKC inhibitor STS and should be considered for AAT augmentation therapies in future.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sarabhai, Theresia UNSPECIFIED UNSPECIFIED UNSPECIFIED Peter, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Baer, Anne-Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Windolf, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Relja, Borna UNSPECIFIED orcid.org/0000-0002-5625-8823 UNSPECIFIED Wesselborg, Sebastian UNSPECIFIED orcid.org/0000-0002-5236-942X UNSPECIFIED Wahlers, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Paunel-Goerguelue, Adnana UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-231205
DOI:	10.1371/journal.pone.0177450
Journal or Publication Title:	PLoS One
Volume:	12
Number:	5
Date:	2017
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROGRAMMED CELL-DEATH; TRAUMA; ACTIVATION; INHIBITOR; SEPSIS; ALPHA; LEADS; GENE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23120