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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 4, 2005; DOI: 10.1124/jpet.105.084434

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Received for publication February 11, 2005.
Revised July 29, 2005.
Accepted for publication August 1, 2005.

Curcumin suppresses interleukin 1{beta}-mediated microsomal prostaglandin E synthase 1 (mPGES-1) by altering early growth response gene EGR-1 and other signaling pathways

Yuseok Moon 1, Wayne C Glasgow 2, Thomas E. Eling 3*

1 NIEHS 2 Mercer University School of Medicine 3 NIH, NIEHS

* Address correspondence to: E-mail: eling{at}niehs.nih.gov

Abstract

Curcumin (diferuloylmethane) is one of the phytophenolic compounds found in the turmeric plant with anti- inflammatory and anti-carcinogenic activities. One possible mechanism for these activities is the inhibition of prostaglandin E2 formation. In this study and other reports, curcumin suppresses interleukin-1{beta}-induced formation of PGE2 in a concentration-dependent manner. Interleukin-1{beta}-induced mPGES-1 and cyclooxygenase-2 were attenuated by curcumin at the protein and mRNA levels, but a more dramatic inhibition of mPGES-1 expression was observed at lower concentrations of curcumin in A549 human lung epithelial cells. The inhibition of mPGES-1 expression by curcumin shifted the arachidonic acid profile from PGE2 to PGF2{alpha} and 6-keto-PGF1{alpha} as major metabolites. The expression of EGR-1, a key transcription factor of cytokine-induced mPGES-1, was inhibited by curcumin. Incubation with siRNA for EGR-1 inhibited IL-1{beta}-induced mPGES-1 and the controlled expression of EGR-1 increased the mPGES-1 expression. Several pro-inflammatory signaling molecules such as NF- {kappa}B and MAP kinases are also known to affect curcumin- regulated gene expression. Curcumin inhibited I{kappa}B{alpha} phosphorylation and degradation and thus reduced the expression of mPGES-1. Curcumin suppressed cytokine- induced mPGES-1 by inhibiting phosphorylation of Jun N- terminal kinase (JNK)1/2. However, EGR-1 expression was suppressed by lower concentrations of curcumin, as compared to JNK1/2 and IkB{alpha}. These results indicate that curcumin inhibits IL-1{beta}-induced PGE2 formation by inhibiting the expression of mPGES-1 that is mediated by suppression of EGR-1 expression as well as NF-{kappa}B and JNK1/2.


Key words: Prostaglandin, cancinogenesis, curcumin, cyclooxygenase, inflammation, mPGES-1


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B. Samuelsson, R. Morgenstern, and P.-J. Jakobsson
Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target
Pharmacol. Rev., September 1, 2007; 59(3): 207 - 224.
[Abstract] [Full Text] [PDF]


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