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

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.
AuthorsSung Keun Jung, Su Jeong Ha, Yeong A Kim, Jihoon Lee, Tae-Gyu Lim, Yun Tai Kim, Nam Hyouck Lee, Jun Seong Park, Myeong-Hun Yeom, Hyong Joo Lee, Ki Won Lee
JournalJournal of cellular and molecular medicine (J Cell Mol Med) Vol. 19 Issue 1 Pg. 135-42 (Jan 2015) ISSN: 1582-4934 [Electronic] England
PMID25176057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Chemical References
  • Flavonoids
  • Transcription Factor AP-1
  • Cyclooxygenase 2
  • MAP Kinase Kinase Kinases
  • mitogen-activated protein kinase kinase kinase 11
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • Dinoprostone
  • dehydroglyasperin D
Topics
  • Animals
  • Cell Survival (drug effects, radiation effects)
  • Cyclooxygenase 2 (metabolism)
  • Dinoprostone (biosynthesis)
  • Female
  • Flavonoids (chemistry, pharmacology)
  • Gene Knockdown Techniques
  • Humans
  • Keratinocytes (drug effects, enzymology, radiation effects)
  • MAP Kinase Kinase 3 (metabolism)
  • MAP Kinase Kinase 6 (metabolism)
  • MAP Kinase Kinase Kinases (metabolism)
  • MAP Kinase Signaling System (drug effects, radiation effects)
  • Mice, Hairless
  • Phosphorylation (drug effects, radiation effects)
  • Protein Binding (drug effects, radiation effects)
  • Transcription Factor AP-1 (metabolism)
  • Ultraviolet Rays

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