4.7 Article

Induction of Heme Oxygenase-1 by 15d-Prostaglandin J2 Mediated via a ROS-Dependent Sp1 and AP-1 Cascade Suppresses Lipopolysaccharide-Triggered Interleukin-6 Expression in Mouse Brain Microvascular Endothelial Cells

期刊

ANTIOXIDANTS
卷 11, 期 4, 页码 -

出版社

MDPI
DOI: 10.3390/antiox11040719

关键词

HO-1; 15d-PGJ(2); bEnd; 3; ROS; interleukin-6; lipopolysaccharide; Sp1; AP-1

资金

  1. Ministry of Science and Technology, Taiwan [MOST109-2320-B-039-061, MOST110-2320-B-039-071]
  2. China Medical University, Taiwan [CMU110-MF-05]
  3. Chang Gung Medical Research Foundation, Taiwan [CMRPG5J0143, CMRPG5L0181]

向作者/读者索取更多资源

15d-PGJ(2) induces the expression of HO-1 in bEnd.3 cells through the activation of NOX- and mitochondria-derived ROS-dependent PKC delta/JNK1/2/Sp1/AP-1 signaling pathway, thus protecting against inflammatory responses.
Heme oxygenase-1 (HO-1) has been shown to exert antioxidant, anti-inflammatory, and anti-apoptotic effects in various types of cells. Therefore, the induction of HO-1 is an excellent rationale for the development of protective drugs. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) can modulate the expression of antioxidant defense proteins and be beneficial for neuroinflammation. Brain endothelial cells play an important role in the pathophysiology of brain disorders. Whether 15d-PGJ(2) can induce HO-1 expression and protect against the inflammatory responses in mouse brain microvascular endothelial (bEnd.3) cells remains unclear. Here, we reveal that 15d-PGJ(2) stimulated HO-1 protein and mRNA expression in a time- and concentration-dependent manner in bEnd.3 cells, which was attenuated by diphenyleneiodonium chloride (DPI) and MitoTempo. Thus, activation of NADPH oxidase (NOX)- and mitochondria-derived reactive oxygen species (ROS) mediated 15d-PGJ(2)-induced HO-1 expression. ROS generation could cause phosphorylation of protein kinase C (PKC)delta, leading to HO-1 expression, which was suppressed by Rottlerin (selective inhibitor PKC delta), DPI, and MitoTempo. We further demonstrated that phosphorylation of c-Jun N-terminal kinase (JNK)1/2 participated in 15d-PGJ(2)-upregulated HO-1 expression, which was blocked by SP600125 or Rottlerin. Moreover, 15d-PGJ(2)-induced HO-1 expression was mediated through the activation of c-Jun (a subunit of activator protein 1 (AP-1)) and specificity protein 1 (Sp1), leading to their interaction with the HO-1 promoter, revealed by chromatin immunoprecipitation assay, which was attenuated by SP600125, Mithramycin A, or Tanshinone II A. We further verified the anti-inflammatory effect of HO-1 expression. Our results showed that 15d-PGJ(2)-induced HO-1 could mitigate the lipopolysaccharide-triggered interleukin-6 expression and secretion, as measured by an ELISA assay kit. These results suggest that 15d-PGJ(2)-induced HO-1 expression is mediated through the activation of NOX- and mitochondria-derived ROS-dependent PKC delta/JNK1/2/Sp1 and the AP-1 signaling pathway and protects against inflammatory responses in bEnd.3 cells.

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