2-Methoxyestradiol attenuates liver fibrosis in mice: implications for M2 macrophages
Liver fibrosis is a major health problem worldwide due to its serious complications including cirrhosis and liver cancer. 2-Methoxyestradiol (2-ME) is an end metabolite of estradiol with anti-proliferative, antioxidant, and anti-inflammatory activities. However, the protective role of 2-ME in liver fibrosis has not been fully investigated. The aim of this study was to determine the protective effect of 2-ME in carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Animals were injected intraperitoneally with CCl4 twice weekly for 6 weeks. 2-ME 50 mg/kg or 100 mg/kg was administrated intraperitoneally every day over the same period. Our data showed that 2-ME reduced the extent of liver toxicity and fibrosis due to CCl4 exposure. It restored the elevated serum liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels and ameliorated oxidative status. In addition, 2-ME significantly reduced collagen deposition and alpha-smooth muscle actin (α-SMA) protein expressions. Furthermore, 2-ME markedly lowered macrophage infiltration and macrophage alternative activation marker chitinase-like molecules (CHI3L3/YM1). The results of this study indicate an important protective activity of 2-ME in liver fibrosis and highlight the role of macrophage recruitment and alternative activation as a possible target.
Keywords2-Methoxyestradiol Liver fibrosis Carbon tetrachloride Macrophages Alternative activation
The project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. G-252-249-38. The authors, therefore, acknowledge with thanks DSR for technical and financial support.
TN and AA conceived and designed research. AA and AH participated in the biochemical and immunohistochemical studies. BE contributed new reagents and antibodies. TN performed the real-time polymerase chain reaction. TN, BE, and AA analyzed the data. TN wrote the manuscript. All authors revised and approved the manuscript.
The project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. (G-252-249-38).
Compliance with ethical standards
The study was carried out in accordance with ethical standards in all aspects.
Conflict of interest
The authors declare that they have no conflict of interest.
- Abdel-Naim AB, Neamatallah T, Eid BG, Esmat A, Alamoudi AJ, Abd El-Aziz GS, Ashour OM (2018) 2-Methoxyestradiol Attenuates Testosterone-Induced Benign Prostate Hyperplasia in Rats through Inhibition of HIF-1α/TGF-β/Smad2 Axis. Oxidative Med Cell Longev 2018:4389484Google Scholar
- Aquino-Galvez A, Gonzalez-Avila G, Delgado-Tello J, Castillejos-Lopez M, Mendoza-Milla C, Zuniga J, Checa M, Maldonado-Martinez HA, Trinidad-Lopez A, Cisneros J, Torres-Espindola LM, Hernandez-Jimenez C, Sommer B, Cabello-Gutierrez C, Gutierrez-Gonzalez LH (2016) Effects of 2-methoxyestradiol on apoptosis and HIF-1alpha and HIF-2alpha expression in lung cancer cells under normoxia and hypoxia. Oncol Rep 35:577–583CrossRefPubMedGoogle Scholar
- Bruce JY, Eickhoff J, Pili R, Logan T, Carducci M, Arnott J, Treston A, Wilding G, Liu G (2012) A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate. Investig New Drugs 30:794–802CrossRefGoogle Scholar
- Dahut WL, Lakhani NJ, Gulley JL, Arlen PM, Kohn EC, Kotz H, McNally D, Parr A, Parr A, Nguyen D, Yang SX, Steinberg SM, Venitz J, Sparreboom A, Figg II W (2014) Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors. Cancer Biology & Therapy 5(1):22–27. https://doi.org/10.4161/cbt.5.1.2349
- Harrison MR, Hahn NM, Pili R, Oh WK, Hammers H, Sweeney C, Kim K, Perlman S, Arnott J, Sidor C, Wilding G, Liu G (2011) A phase II study of 2-methoxyestradiol (2ME2) NanoCrystal® dispersion (NCD) in patients with taxane-refractory, metastatic castrate-resistant prostate cancer (CRPC). Invest New Drugs 29:1465–1474CrossRefPubMedGoogle Scholar
- Heymann F, Hammerich L, Storch D, Bartneck M, Huss S, Rüsseler V, Gassler N, Lira SA, Luedde T, Trautwein C, Tacke F (2012) Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice. Hepatology (Baltimore, Md.) 55:898–909CrossRefGoogle Scholar
- Kang S-H, Cho HT, Devi S, Zhang Z, Escuin D, Liang Z, Mao H, Brat DJ, Olson JJ, Simons JW, LaVallee TM, Giannakakou P, Van Meir EG, Shim H (2006) Antitumor effect of 2-Methoxyestradiol in a rat orthotopic brain tumor model. Cancer Res 66(24):11991–11997. https://doi.org/10.1158/0008-5472.CAN-06-1320
- López-Navarrete G, Ramos-Martínez E, Suárez-Álvarez K, Aguirre-García J, Ledezma-Soto Y, León-Cabrera S, Gudiño-Zayas M, Guzmán C, Gutiérrez-Reyes G, Hernández-Ruíz J, Camacho-Arroyo I, Robles-Díaz G, Kershenobich D, Terrazas LI, Escobedo G (2011) Th2-associated alternative Kupffer cell activation promotes liver fibrosis without inducing local inflammation. Int J Biol Sci 7:1273–1286. https://doi.org/10.7150/ijbs.7.1273
- Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7(2):27–31. https://doi.org/10.4103/0976-0105.177703
- Nair MG, Gallagher IJ, Taylor MD, Loke P, Coulson PS, Wilson RA, Maizels RM, Allen JE (2005) Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun 73:385–394CrossRefPubMedPubMedCentralGoogle Scholar
- Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, Hartland SN, Snowdon VK, Cappon A, Gordon-Walker TT, Williams MJ, Dunbar DR, Manning JR, Van Rooijen N, Fallowfield JA, Forbes SJ, Iredale JP (2012) Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 109:E3186–E3195CrossRefPubMedPubMedCentralGoogle Scholar
- DOI: 10.7150/ijbs.7.1273Google Scholar