Up-regulation of heme oxygenase-1 expression through CaMKII-ERK1/2-Nrf2 signaling mediates the anti-inflammatory effect of bisdemethoxycurcumin in LPS-stimulated macrophages

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Title
Up-regulation of heme oxygenase-1 expression through CaMKII-ERK1/2-Nrf2 signaling mediates the anti-inflammatory effect of bisdemethoxycurcumin in LPS-stimulated macrophages
Author(s)
A N Kim; W K Jeon; Jung Joon Lee; B C Kim
Bibliographic Citation
Free Radical Biology and Medicine, vol. 49, no. 3, pp. 323-331
Publication Year
2010
Abstract
We have identified a novel anti-inflammatory signaling pathway that leads to the expression of heme oxygenase-1 (HO-1) in response to bisdemethoxycurcumin (BDMC), an analog of curcumin. Treatment with BDMC suppressed inducible nitric oxide synthase expression and nitric oxide (NO) production by down-regulating NF-κB activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. These effects were reversed by blocking HO-1 activity or expression. The signaling pathway involved in BDMC-mediated HO-1 induction included Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase 1/2 (ERK1/2). BDMC induced phosphorylation of ERK1/2 in a CaMKII-dependent manner. Pretreatment with the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor, U0126, inhibited CaMKII-induced stimulation of HO-1 promoter activity, suggesting that ERK1/2 is a downstream mediator of CaMKII in BDMC signaling to HO-1 expression. Furthermore, the CaMKII-ERK1/2 cascade targets the transcription factor, NF-E2-related factor-2 (Nrf2). Finally, inhibition of the Ca2+-CaMKII-ERK1/2-linked cascade attenuated significantly suppression by BDMC of LPS-induced iNOS expression and subsequent NO production. Collectively, our findings identify a Ca2+/calmodulin-CaMKII-ERK1/2-Nrf2 cascade as a novel anti-inflammatory pathway mediating BDMC signaling to HO-1 expression in macrophages.
Keyword
Anti-inflammatoryBDMCHO-1MacrophagesCaMKII
ISSN
0891-5849
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.freeradbiomed.2010.04.015
Type
Article
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1. Journal Articles > Journal Articles
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