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Cigarette smoke extracts and cadmium induce COX-2 expression through γ-secretase-mediated p38 MAPK..
  • 작성일2020-05-07
  • 최종수정일2020-05-07
  • 담당부서연구기획과
  • 연락처043-719-8033
  • 293

PLOS ONE, 2019. 14(2), e0212749-, DOI: https://doi.org/10.1371/journal.pone.0212749


Cigarette smoke extracts and cadmium induce COX-2 expression through γ-secretase-mediated p38 MAPK activation in C6 astroglia cells

Hyun Joung Lim, Jung Hyun Park;Chulman Jo;Keejung Yoon;Young Ho Koh


Abstract

    Exposure to cigarette smoke has been implicated in the progression of cerebrovascular and neurological disorders like stroke through inflammation and blood-brain barrier disruption. In this study, we investigated the signaling cascade activated by cigarette smoke extracts(CSE) and cadmium (Cd) resulting in the COX-2 induction in C6 rat astroglia cells. CSE or Cd induced Notch1 cleavage and activated p38 MAPK and CREB signaling pathways in C6 astroglia cells. Knockdown of nicastrin using siRNA or γ secretase inhibitors, DAPT and L- 685,486, reduced Notch1 cleavage and phosphorylation of p38 MAPK and CREB, while phosphorylation of ERK and JNK remained unaffected. Additionally, the blockage of γ- secretase activity did not show any effect on the phosphorylation of AKT, another upstream activator of CREB, indicating that γ-secretase-mediated CREB activation occurs via p38 MAPK. γ-secretase inhibitor also inhibited the CSE and Cd-mediated increase in the expression of COX-2. Furthermore, recombinant overexpression of Notch1 intracellular domain resulted in an increase in the expression of COX-2. Notch signaling induced by CSE and Cd induced apoptosis in C6 cells. Our results demonstrate that CSE exposure activated the p38 MAPK and CREB-mediated induction in COX-2 expression in astrocytes via γ-secretase-mediated Notch1 signaling. Our data provides novel insights into the potential mechanism of pro-inflammatory response activated by exposure to cigarette smoke.



  • 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
  • This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.


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