title: Curcumin suppresses interleukin 1beta-mediated microsomal prostaglandin E synthase 1 by altering early growth response gene 1 and other signaling pathways.
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) E(2) formation. In this study and other reports, curcumin suppresses interleukin-1beta-induced formation of prostaglandin E(2) in a concentration-dependent manner. Interleukin-1beta-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 PGE(2) to PGF(2alpha) and 6-keto-PGF(1alpha) 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)-1beta-induced mPGES-1, and the controlled expression of EGR-1 increased the mPGES-1 expression. Several proinflammatory signaling molecules, such as nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinases, are also known to affect curcumin-regulated gene expression. Curcumin inhibited IkappaBalpha 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 IkappaBalpha. These results indicate that curcumin inhibits IL-1beta-induced PGE(2) formation by inhibiting the expression of mPGES-1 that is mediated by suppression of EGR-1 expression as well as NF-kappaB and JNK1/2.
authors.affiliation: Eicosanoid Biochemistry Section, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Glasgow
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eling
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D000071876:Prostaglandin-E Synthases; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D051766:Early Growth Response Protein 1; D007375:Interleukin-1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D016718:Arachidonic Acid; D008156:Luciferases; D051546:Cyclooxygenase 2; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D003474:Curcumin