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



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.


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.


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.


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.


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


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

13273_2018_43_MOESM1_ESM.pdf (248 kb)
PGA2-induced expression of HO-1 is mediated by transcriptional upregulation of Nrf2


  1. 1.
    Straus, D. S. & Glass, C. K. Cyclopentenone prostaglandins: new insights on biological activities and cellular targets. Med Res Rev 21, 185–210 (2001).CrossRefGoogle Scholar
  2. 2.
    Rossi, A. et al. Anti–inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000).CrossRefGoogle Scholar
  3. 3.
    Hubich, A. I. & Sholukh, M. V. Biochemistry of Prostaglandins A. Biochemistry 71, 229–238 (2006).Google Scholar
  4. 4.
    Choe, Y. J. et al. PGA2–induced HO–1 attenuates G2M arrest by modulating GADD45α expression. Mol Cell Toxicol 11, 465–474 (2015).CrossRefGoogle Scholar
  5. 5.
    Zenkov, N. K., Menshchikova, E. B. & Tkachev, V. O. Keap1/Nrf2/ARE redox–sensitive signaling system as a pharmacological target. Biochemistry 78, 19–36 (2013).Google Scholar
  6. 6.
    Suzuki, T. & Yamamoto, M. Molecular basis of the Keap1–Nrf2 system. Free Radic Biol Med 88, 93–100 (2015).CrossRefGoogle Scholar
  7. 7.
    Sihvola, V. & Levonen, A.–L. Keap1 as the redox sensor of the antioxidant response. Arch Biochem Biophys 617, 94–100 (2017).CrossRefGoogle Scholar
  8. 8.
    Haskew–Layton, R. E., Payappilly, J. B., Xu, H., Bennett, S. A. & Ratan, R. R. 15–Deoxy–Δ12,14–prostaglandin J2 (15d–PGJ2) protects neurons from oxidative death via a. Nrf2 astrocyte–specific mechanism independent of PPARgamma. J Neurochem 124, 536–547 (2013).CrossRefGoogle Scholar
  9. 9.
    Koyani, C. N. et al. Activation of the MAPK/Akt/Nrf2–Egr1/HO–1–GCLc axis protects MG–63 osteosarcoma cells against 15d–PGJ2–mediated cell death. Biochem Pharmacol 104, 29–41 (2016).CrossRefGoogle Scholar
  10. 10.
    Kansanen, E., Kivela, A. M. & Levonen, A. L. Regulation of Nrf2–dependent gene expression by 15–deoxy–Δ12,14–prostaglandin J2. Free Radic Biol Med 47, 1310–1317 (2009).CrossRefGoogle Scholar
  11. 11.
    Remy, G. et al. Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal 22, 660–667 (2010).CrossRefGoogle Scholar
  12. 12.
    Kocanova, S. et al. Induction of heme–oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin–mediated photodynamic therapy. Apoptosis 12, 731–741 (2007)CrossRefGoogle Scholar
  13. 13.
    Kim, Y. M., Kim, H. J. & Chang, K. C. Glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide–activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2–dependent induction of HO–1. Int Immunopharmacol 26, 112–118 (2015).CrossRefGoogle Scholar
  14. 14.
    Santoro, M. G., Garaci, E. & Amici, C. Prostaglandins with antiproliferative activity induce the synthesis of a heat shock protein in human cells. Proc Natl Acad Sci USA 86, 8407–8411 (1989).CrossRefGoogle Scholar
  15. 15.
    Amici, C., Sistonen, L., Santoro, M. G. & Morimoto, R. I. Antiproliferative prostaglandins activate heat shock transcription factor. Proc Natl Acad Sci USA 89, 6227–6231 (1992).CrossRefGoogle Scholar
  16. 16.
    Baird, L., Swift, S., Llères, D. & Dinkova–Kostova, A. T. Monitoring Keap1–Nrf2 interactions in single live cells. Biotechnol Adv 32, 1133–1144 (2014).CrossRefGoogle Scholar
  17. 17.
    Lu, M. C., Ji, J. A., Jiang, Z. Y. & You, Q. D. The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update. Med Res Rev 36, 924–63 (2016).CrossRefGoogle Scholar
  18. 18.
    Lee, D. H., Gold, R. & Linker, R. A. Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci 13, 11783–803 (2012).CrossRefGoogle Scholar
  19. 19.
    Grzegorzewska, A. P. et al. Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep 7, 41605 (2017).CrossRefGoogle Scholar
  20. 20.
    Hong, Y. A. et al. Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO–1 signaling. J Transl Med. 12, 50 (2014).CrossRefGoogle Scholar
  21. 21.
    Sheremata, W., Brown, A. D. & Rammohan, K. W. Dimethyl fumarate for treating relapsing multiple sclerosis. Expert Opin Drug Saf 14, 161–170 (2015).CrossRefGoogle Scholar
  22. 22.
    Lijnen, R., Otters, E., Balak, D. & Thio, B. Long–term safety and effectiveness of high–dose dimethylfumarate in the treatment of moderate to severe psoriasis: a prospective single–blinded follow–up study. J Dermatolog Treat 27, 31–36 (2016).CrossRefGoogle Scholar
  23. 23.
    Kim, H. S., Rhim, H., Jeong, S. W., Kim, J. W. & Kim, I. K. Induction of apoptosis dependent on caspase activities and growth arrest in HL–60 cells by PGA2. Prostaglandins Other Lipid Mediat 70, 169–183 (2002).CrossRefGoogle Scholar
  24. 24.
    Lee, J. H., Kim, H. S., Jeong, S. Y. & Kim, I. K. Induction of p53 and apoptosis by Δ12–PGJ2 in human hepatocarcinoma SK–HEP–1 cells. FEBS Lett 368, 348–352 (1995).CrossRefGoogle Scholar
  25. 25.
    Ahn, S. G. et al. Sox–4 is a positive regulator of Hep3B and HepG2 cells’ apoptosis induced by prostaglandin (PG)A2 and Δ12–PGJ2. Exp Mol Med 34, 243–249 (2002).CrossRefGoogle Scholar

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

Personalised recommendations