Volume 7 Supplement 1

12th Joint Meeting of the Signal Transduction Society (STS). Signal Transduction: Receptors, Mediators and Genes

Open Access

An atypical NF-kappa B-regulated pathway mediates phorbol ester-dependent Heme oxygenase-1 gene activation in monocytes

  • S Naidu1,
  • N Wijayanti1,
  • S Santoso1,
  • T Kietzmann2 and
  • S Immenschuh1
Cell Communication and Signaling20097(Suppl 1):A6

DOI: 10.1186/1478-811X-7-S1-A6

Published: 26 February 2009

Heme oxygenase (HO)-1 is the rate-limiting enzyme of heme degradation. More recently, HO-1 has been shown to have anti-inflammatory and antioxidant functions, which have been demonstrated in HO-1 knockout mice models and a human case of HO-1 genetic deficiency. Moreover, targeted induction of HO-1 has been shown to have therapeutic effects in various disease models. Here, it is reported that the HO-1 gene is transcriptionally induced by the phorbol ester phorbol myristate acetate (PMA), which is a prototypical activator of PKC, in various monocytic cells. The PMA-dependent induction of HO-1 has a different time-dependent pattern of induction from that of lipopolysaccharide-dependent HO-1 induction in these cells. Activation of HO-1 by PMA was mediated via a newly identified kB element of the proximal rat HO-1 gene promoter region (-284 to -275). This HO-kB element was a nuclear target for the NF-kB 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 IkB, but not by dominant negative IkB kinase-2 (IKK2) suggesting that the classical NF-kB 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 activation of p38 MAPK by PMA was independent of CK2. Taken together, induction of HO-1 gene expression by PMA is regulated via an IKK-independent atypical NF-kB pathway that is mediated via activation of p38 MAPK and CK2.

Authors’ Affiliations

(1)
Institute for Clinical Immunology and Transfusion Medicine, Uni-Klinikum Giessen
(2)
Department of Biochemistry, University of Kaiserslautern

Copyright

© Naidu et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

Advertisement