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An Atypical NF-B-Regulated Pathway Mediates Phorbol Ester-Dependent Heme Oxygenase-1 Gene Activation in Monocytes¹

Srivatsava Naidu^*, Nastiti Wijayanti^*, Sentot Santoso^*, Thomas Kietzmann and Stephan Immenschuh^2,*

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

Heme oxygenase (HO)-1 catalyzes the rate-limiting step of heme degradation and plays an important anti-inflammatory role via its enzymatic products carbon monoxide and biliverdin. In this study it is reported that the HO-1 gene is transcriptionally induced by the phorbol ester PMA in cell cultures of monocytic cells with a regulatory pattern that is different from that of LPS-dependent HO-1 induction in these cells. Activation of HO-1 by PMA was mediated via a newly identified B element of the proximal rat HO-1 gene promoter region (–284 to –275). This HO-B element was a nuclear target for the NF-B subunit p65/RelA as determined by nuclear binding assays and transfection experiments with luciferase reporter gene constructs in RAW264.7 monocytes. Moreover, PMA-dependent induction of endogenous HO-1 gene expression and promoter activity was abrogated in embryonic fibroblasts from p65^–/– mice. PMA-dependent HO-1 gene activation was reduced by an overexpressed dominant negative mutant of IB, but not by dominant negative IB kinase-2, suggesting that the classical NF-B pathway was not involved in this regulation. The antioxidant N-acetylcysteine and inhibitors of p38 MAPK or serine/threonine kinase CK2 blocked PMA-dependent HO-1 gene activation. Finally, it is demonstrated by luciferase assays with a Gal4-CHOP fusion protein that the activation of p38 MAPK by PMA was independent of CK2. Taken together, induction of HO-1 gene expression by PMA is regulated via an IB kinase-independent, atypical NF-B pathway that is mediated via the activation of p38 MAPK and CK2.

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 Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, Langhansstrasse 7, 35392 Giessen, Germany. E-mail address: Stephan.Immenschuh{at}med.uni-giessen.de

³ Abbreviations used in this paper: HO, heme oxygenase; IKK, I-B kinase; LTM, liver tissue macrophage; MEF, mouse embryonic fibroblast; MTE, macrophage-specific 12-O-tetradecanoyl-phorbol-13-acetate-responsive element; NAC, N-acetylcysteine; NE, nuclear extracts; Nrf2, NF-E2-related factor-2; PKC, protein kinase C; RE, regulatory element; RFBD, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole; ROS, reactive oxygen species; TF, transcription factor.

This article has been cited by other articles:

				S. Naidu, V. Vijayan, S. Santoso, T. Kietzmann, and S. Immenschuh Inhibition and Genetic Deficiency of p38 MAPK Up-Regulates Heme Oxygenase-1 Gene Expression via Nrf2 J. Immunol., June 1, 2009; 182(11): 7048 - 7057. [Abstract] [Full Text] [PDF]