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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901264v1 183/10/6198    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Paunel-Görgülü, A. Articles by Scholz, M. PubMed PubMed Citation Articles by Paunel-Görgülü, A. Articles by Scholz, M.

Mcl-1-Mediated Impairment of the Intrinsic Apoptosis Pathway in Circulating Neutrophils from Critically Ill Patients Can Be Overcome by Fas Stimulation¹

Adnana Paunel-Görgülü,^* Martin Zörnig, Tim Lögters,^* Jens Altrichter,^* Uta Rabenhorst, Jindrich Cinatl, Joachim Windolf,^* and Martin Scholz^2*

^*Department of Traumatology and Hand Surgery, Heinrich-Heine University, Duesseldorf, Germany; Georg Speyer Haus, Frankfurt am Main, Germany; and Institute for Medical Virology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany

The systemic inflammatory response syndrome and subsequent organ failure are mainly driven by activated neutrophils with prolonged life span, which is believed to be due to apoptosis resistance. However, detailed underlying mechanisms leading to neutrophil apoptosis resistance are largely unknown, and possible therapeutic options to overcome this resistance do not exist. Here we report that activated neutrophils from severely injured patients exhibit cell death resistance due to impaired activation of the intrinsic apoptosis pathway, as evidenced by limited staurosporine-induced mitochondrial membrane depolarization and decreased caspase-9 activity. Moreover, we found that these neutrophils express high levels of antiapoptotic Mcl-1 and low levels of proapoptotic Bax protein. Mcl-1 up-regulation was dependent on elevated concentrations of GM-CSF in patient serum. Accordingly, increased Mcl-1 protein stability and GM-CSF serum concentrations were shown to correlate with staurosporine-induced apoptosis resistance. However, cross-linking of neutrophil Fas by immobilized agonistic anti-Fas IgM resulted in caspase-dependent mitochondrial membrane depolarization and apoptosis induction. In conclusion, the observed impairment of the intrinsic pathway and the resulting apoptosis resistance may be overcome by immobilized agonistic anti-Fas IgM. Targeting of neutrophil Fas by immobilized agonistic effector molecules may represent a new therapeutic tool to limit neutrophil hyperactivation and its sequelae in patients with severe immune disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Bundesministerium für Wirtschaft und Technologie (to A.P.-G.), Deutsche Forschungsgemeinschaft Grants SCHO 612/3-1 (to M.S.) and ZO 110/4-1 (to M.Z.), Wilhelm Sander-Stiftung Grant 2008.091.1 (to M.Z.), and Graduiertenkolleg Grant 1172 (to U.R.).

² Address correspondence and reprint requests to Prof. Dr. Martin Scholz, Department of Traumatology and Hand Surgery, University Hospital Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany. E-mail address: martin.scholz{at}uni-duesseldorf.de

³ Abbreviations used in this paper: MODS, multiple organ dysfunction syndrome; ICU, intensive care unit; PI, propidium iodide; PU, polyurethane; SIRS, systemic inflammatory response syndrome; TBS-T, Tris-buffered saline containing 0.1% Tween 20.