Piceatannol inhibits phorbol ester-induced expression of COX-2 and iNOS in HR-1 hairless mouse skin by blocking the activation of NF-κB and AP-1.
OBJECTIVE
The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory activity of piceatannol (trans-3,4,3',5'-tetrahydroxystilbene) in mouse skin in vivo.


METHODS
Female HR-1 hairless mice were topically treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) with or without piceatannol pretreatment. Epidermal protein expression was assessed by Western blot analysis. The cyclooxygenase-2 (COX-2) expression was detected by immunohistochemistry. The DNA binding of nuclear factor-kappaB (NF-κB) and activator protein-1 (AP-1) was examined by the electrophoretic mobility gel shift assay. The catalytic activity of IκBα kinase-β (IKKβ) was measured by in vitro kinase assay.


RESULTS
Pretreatment with piceatannol attenuated TPA-induced expression of COX-2 and inducible nitric oxide synthase (iNOS) in mouse skin. Piceatannol diminished nuclear translocation and the DNA binding of NF-κB through the blockade of phosphorylation and subsequent degradation of IκBα. Piceatannol attenuated the catalytic activity of IKKβ and inhibited the phosphorylation of mitogen-activated protein (MAP) kinases in TPA-treated mouse skin. In addition, piceatannol decreased TPA-induced expression of c-Fos and the DNA binding of AP-1.


CONCLUSIONS
Piceatannol inhibits TPA-induced COX-2 and iNOS expression by blocking the activation of NF-κB and AP-1 via suppression of the IKKβ activity and phosphorylation of MAP kinases, which provides a mechanistic basis of its anti-inflammatory effects in mouse skin.
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
Lijia
L
Liu
Jianchun
J
Li
Joydeb Kumar
JK
Kundu
Young-Joon
YJ
Surh
D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D051550:I-kappa B Kinase / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D013267:Stilbenes; D018808:Transcription Factor AP-1; C041525:3,3',4,5'-tetrahydroxystilbene; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D013755:Tetradecanoylphorbol Acetate