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Molecular & Cellular Toxicology

, Volume 14, Issue 4, pp 391–398 | Cite as

PGA2-induced expression of HO-1 is mediated by transcriptional upregulation of Nrf2

  • Sang-sun Lee
  • Yun-Jeong Choe
  • Hyein Lee
  • Sun-Young Lee
  • Ho-Shik KimEmail author
Original Paper
  • 26 Downloads

Abstract

Backgrounds

Prostaglandin (PG) A2 reportedly stimulated expression of heme oxygenase(HO)-1 at the level of transcription via the activation of p38MAPK. Details of the mechanism, however, have not been provided, and this includes identification of the transcription factors responsible for PGA2-induced HO-1 expression. Herein is described an analysis of the role of nuclear factor erythroid 2 related factor 2 (Nrf2) and how PGA2 increases the activity of Nrf2 during PGA2-induced HO-1 expression.

Methods

Expressions of HO-1 and Nrf2 were analyzed at the levels of both mRNA and protein. Nrf2 siRNA, SB203580, an inhibitor of p38MAPK, and scavengers of reactive oxygen species (ROS) were used to identify the effects of Nrf2, p38MAPK and ROS on PGA2-induced HO-1 expression.

Results

Although SB203580 suppressed PGA2-induced HO-1 expression, genetic activation of p38MAPK could not stimulate the transcription of HO-1. Cycloheximide (CHX), an inhibitor of protein translation, almost completely prevented PGA2-induced increase of HO-1 transcription, but it did not prevent the phosphorylation of p38MAPK, which suggests that both de novo protein synthesis and p38MAPK activity are required to induce the transcription of HO-1 in response to PGA2 treatment. In addition, PGA2 increased the level of both Nrf2 mRNA and protein in a dose-dependent manner. Knockdown of Nrf2 using small interfering RNA (siRNA) suppressed PGA2-induced HO-1 expression. The PGA2-induced transcription of Nrf2 was prevented by ROS scavengers such as n-acetyl-l-cysteine and tempol but not CHX. Furthermore, siRNA against p38MAPK did not change the level of nuclear Nrf2 protein.

Conclusion

These findings suggest that PGA2 induces HO-1 transcription via an increase in Nrf2 protein, the transcription of which is initiated by an accumulation of ROS that is independent of the p38MAPK activation pathway.

Keywords

Prostaglandin A2 Heme oxygenase-1 Nuclear factor erythroid 2 related factor 2 p38MAPK 

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Supplementary material

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PGA2-induced expression of HO-1 is mediated by transcriptional upregulation of Nrf2

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Copyright information

© The Korean Society of Toxicogenomics and Toxicoproteomics and Springer Nature B.V. 2018

Authors and Affiliations

  • Sang-sun Lee
    • 1
    • 2
  • Yun-Jeong Choe
    • 3
  • Hyein Lee
    • 1
    • 2
  • Sun-Young Lee
    • 1
    • 2
    • 4
  • Ho-Shik Kim
    • 1
    • 2
    Email author
  1. 1.Department of Biochemistry, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
  2. 2.Cancer Evolution Research Center, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
  3. 3.Department of Pharmacy Practice and Pharmaceutical Sciences, College of PharmacyUniversity of MinnesotaDuluthUSA
  4. 4.Department of Biology, Faculty of ScienceNaresuan UniversityPhitsanulokThailand

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