Transcriptional Regulation of Activating Transcription Factor 3 Involves the Early Growth Response-1 Gene

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Abstract
Curcumin (diferuloylmethane) is one of the phytophenolic compounds found in the turmeric plant with anti-inflammatory and anticarcinogenic activities. One possible mechanism for these activities is the inhibition of prostaglandin (PG) E2 formation. In this study and other reports, curcumin suppresses interleukin-1β-induced formation of prostaglandin E2 in a concentration-dependent manner. Interleukin-1β-induced microsomal prostaglandin E synthase 1 (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 PGF2α and 6-keto-PGF1α as major metabolites. The expression of early growth response gene 1 (EGR-1), a key transcription factor of cytokine-induced mPGES-1, was inhibited by curcumin. Incubation with siRNA for EGR-1 inhibited interleukin (IL)-1β-induced mPGES-1, and the controlled expression of EGR-1 increased the mPGES-1 expression. Several proinflammatory signaling molecules, such as nuclear factor κB (NF-κB) and mitogen-activated protein kinases, are also known to affect curcumin-regulated gene expression. Curcumin inhibited IκBα 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 with JNK1/2 and IκBα. These results indicate that curcumin inhibits IL-1β-induced PGE2 formation by inhibiting the expression of mPGES-1 that is mediated by suppression of EGR-1 expression as well as NF-κB and JNK1/2.

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