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Inhibition and Genetic Deficiency of p38 MAPK Up-Regulates Heme Oxygenase-1 Gene Expression via Nrf2¹

Srivatsava Naidu^*, Vijith Vijayan^*, Sentot Santoso^*, Thomas Kietzmann and Stephan Immenschuh^2,*,

^* Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, Giessen, Germany; Department of Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany; and Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany

Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. The HO products carbon monoxide and bilirubin not only provide antioxidant cytoprotection, but also have potent anti-inflammatory and immunomodulatory functions. Although HO-1 has previously been shown to be induced by various stimuli via activation of the p38 MAPK signaling pathway, the role of this protein kinase for HO-1 gene regulation is largely unknown. In the present study, it is demonstrated that pharmacological inhibitors of p38 induced HO-1 expression in monocytic cells. Moreover, basal HO-1 gene expression levels were markedly higher in untreated murine embryonic fibroblasts (MEF) from p38^–/– mice compared with those from wild-type mice. Transfection studies with luciferase reporter gene constructs indicate that increased HO-1 gene expression via inhibition of p38 was mediated by the transcription factor Nrf2, which is a central regulator of the cellular oxidative stress response. Accordingly, inhibitors of p38 induced binding of nuclear proteins to a Nrf2 target sequence of the HO-1 promoter, but did not affect HO-1 protein expression and promoter activity in Nrf2^–/– MEF. Genetic deficiency of p38 led to enhanced phosphorylation of ERK and increased cellular accumulation of reactive oxygen species. In addition, pharmacological blockage of ERK and scavenging of reactive oxygen species with N-acetylcysteine reduced HO-1 gene expression in p38^–/– MEF, respectively. Taken together, it is demonstrated that pharmacological inhibition and genetic deficiency of p38 induce HO-1 gene expression via a Nrf2-dependent mechanism in monocytic cells and MEF.

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 work was supported by a grant from the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 547 and GRK 534 (to S.I. and S.S.).

² Address correspondence and reprint requests to Dr. Stephan Immenschuh, Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail address: Immenschuh.Stephan{at}mh-hannover.de

³ Abbreviations used in this paper: HO, heme oxygenase; CO, carbon monoxide; Cox-2, cyclooxygenase 2; DHE, dihydroethidium; MEF, mouse embryonic fibroblast; NAC, N-acetylcysteine; NE, nuclear extract; ROS, reactive oxygen species; StRE, stress response element; TF, transcription factor; siRNA, small interfering RNA; E2 mut, E2 mutant.