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

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.

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Correspondence to S Naidu.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Naidu, S., Wijayanti, N., Santoso, S. et al. An atypical NF-kappa B-regulated pathway mediates phorbol ester-dependent Heme oxygenase-1 gene activation in monocytes. Cell Commun Signal 7, A6 (2009).

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  • Phorbol Myristate Acetate
  • Phorbol Myristate Acetate
  • Reporter Gene Construct
  • Luciferase Reporter Gene Construct
  • Nuclear Binding Assay