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* Institute of Medical Immunology and
Berlin-Brandenburg Center of Regenerative Therapies, Charité Universitätsmedizin Berlin, Berlin, Germany;
Miltenyi Biotec GmbH, Bergisch Gladbach, Germany;
Therapeutic Human Polyclonals Inc., Mountain View, CA 94043; and
¶ Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
The induction of heme oxygenase 1 (HO-1) by a single treatment with cobalt protoporphyrin (CoPPIX) protects against inflammatory liver failure and ischemia reperfusion injury after allotransplantation. In this context, the HO-1-mediated inhibition of donor-derived dendritic cell maturation and migration is discussed as one of the key events of graft protection. To investigate the poorly understood mechanism of CoPPIX-induced HO-1 activity in more detail, we performed gene expression analysis in murine liver, revealing the up-regulation of STAT3 after CoPPIX treatment. By using wild-type and HO-1-deficient dendritic cells we demonstrated that LPS-induced maturation is dependent on STAT3 phosphorylation and independent of HO-1 activity. In summary, our observations revise our understanding of the anti-inflammatory properties of HO-1 and highlight the immunomodulatory capacity of STAT3, which might be of further interest for targeting undesired immune responses, including ischemia reperfusion injury.
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 M.-F.M. is a recipient of the Charité Graduation grant and the GlaxoSmithKline travel grant. The study was supported by grant N301 08032/3156 from the Ministry of Science and Higher Education and by the European Vascular Genomics Network contract LSHM-CT 2003-503254 (to J.D.). A.J. is the International Senior Research Fellow of Wellcome Trust.
2 Address correspondence and reprint requests to Dr. Katja Kotsch, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, D-10117, Berlin, Germany. E-mail address: katja.kotsch{at}charite.de
3 Abbreviations used in this paper: DC, dendritic cell; BCL3, B cell lymphoma 3; BMDC, bone marrow-derived DC; CO, carbon monoxide; CoPPIX, cobalt-protoporphyrin IX; Ct, cycle threshold; HO-1 heme oxygenase 1; HPRT, hypoxanthine guanine phosphoribosyltransferase; I/R, ischemia reperfusion; MC, methylene chloride; n.s. nonsilencing; PDL-1, programmed death ligand 1; ROS, reactive oxygen species; SnPPIX, tin-protoporphyrin IX; siHO-1, siRNA against HO-1; siRNA, small interfering RNA; siSTAT3, siRNA against STAT3; SOCS3, suppressor of cytokine signaling 3.
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