MLK3 is a novel target of dehydroglyasperin D for the reduction in UVB‐induced COX‐2 expression in vitro and in vivo

Journal of Cellular and Molecular Medicine

Sung Keun Jung¹  Su Jeong Ha⁴  Yeong A Kim¹  Jihoon Lee¹  Tae-Gyu Lim¹  Yun Tai Kim⁴  Nam Hyouck Lee⁴  Jun Seong Park²  Myeong-Hun Yeom²  Hyong Joo Lee³ 

[1] WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Korea;Skin Research Institute, Amorepacific R&D Center, Yongin, Korea;Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Korea;Division of Metabolism and Functionality Research, Korea Food Research Institute, Seongnam, Korea

关键词: dehydroglyasperin D;    cyclooxygenase‐2;    mixed‐lineage kinase 3;    licorice;    inflammation;   

DOI  :  10.1111/jcmm.12311

来源: Wiley

【 摘 要 】

Abstract

Dehydroglyasperin D (DHGA-D), a compound present in licorice, has been found to exhibit anti-obesity, antioxidant and anti-aldose reductase effects. However, the direct molecular mechanism and molecular targets of DHGA-D during skin inflammation remain unknown. In the present study, we investigated the effect of DHGA-D on inflammation and its mechanism of action on UVB-induced skin inflammation in HaCaT human keratinocytes and SKH-1 hairless mice. DHGA-D treatment strongly suppressed UVB-induced COX-2 expression, PGE2 generation and AP-1 transactivity in HaCaT cells without affecting cell viability. DHGA-D also inhibited phosphorylation of the mitogen-activated protein kinase kinase (MKK) 3/6/p38, MAPK/Elk-1, MKK4/c-Jun N-terminal kinase (JNK) 1/2/c-Jun/mitogen, and stress-activated protein kinase (MSK), whereas phosphorylation of the mixed-lineage kinase (MLK) 3 remained unaffected. Kinase and co-precipitation assays with DHGA-D Sepharose 4B beads showed that DHGA-D significantly suppressed MLK3 activity through direct binding to MLK3. Knockdown of MLK3 suppressed COX-2 expression as well as phosphorylation of MKK4/p38 and MKK3/6/JNK1/2 in HaCaT cells. Furthermore, Western blot assay and immunohistochemistry results showed that DHGA-D pre-treatment significantly inhibits UVB-induced COX-2 expression in vivo. Taken together, these results indicate that DHGA-D may be a promising anti-inflammatory agent that mediates suppression of both COX-2 expression and the MLK3 signalling pathway through direct binding and inhibition of MLK3.

【 授权许可】

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© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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