Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes.
The Nrf2/antioxidant response element (ARE) signaling pathway plays a key role in activating cellular antioxidants, including heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), and glutathione. Protein kinase C (PKC) may also regulate these antioxidants, as PKC phosphorylates Nrf2 in vitro. This study examined the role of PKC in ARE-mediated gene regulation in human monocytes by curcumin, a potent inducer of the Nrf2/ARE pathway. Curcumin increased HO-1 and glutamyl cysteine ligase modulator (GCLM) expression and stimulated Nrf2 binding to the ARE. Curcumin also rapidly stimulated PKC phosphorylation and Ro-31-8220, a pan-PKC inhibitor, decreased curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Rottlerin (a PKC delta inhibitor) and PKC delta antisense oligonucleotides significantly inhibited curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Furthermore, a p38 MAP kinase inhibitor reduced GCLM and HO-1 expression and rottlerin inhibited curcumin-induced p38 phosphorylation. In summary, curcumin activates ARE-mediated gene expression in human monocytes via PKC delta, upstream of p38 and Nrf2.
Rushworth
Stuart A
SA
MRC Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Ogborne
Richard M
RM
Charalambos
Charles A
CA
O'Connell
Maria A
MA
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005981:Glutathione Synthase / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000098:Acetophenones; D001578:Benzopyrans; D051267:NF-E2-Related Factor 2; D020319:Oligodeoxyribonucleotides, Antisense; C085746:rottlerin; D051547:Heme Oxygenase-1; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D005981:Glutathione Synthase; D003474:Curcumin