DOI QR코드

DOI QR Code

Arginine Supplementation Recovered the IFN-γ-Mediated Decrease in Milk Protein and Fat Synthesis by Inhibiting the GCN2/eIF2α Pathway, Which Induces Autophagy in Primary Bovine Mammary Epithelial Cells

  • Xia, Xiaojing (College of Veterinary Medicine, Jilin University) ;
  • Che, Yanyi (College of Veterinary Medicine, Jilin University) ;
  • Gao, Yuanyuan (College of Animal Science, Jilin University) ;
  • Zhao, Shuang (College of Animal Science, Jilin University) ;
  • Ao, Changjin (College of Animal Science, Inner Mongolian Agricultural University) ;
  • Yang, Hongjian (College of Animal Science and Technology, China Agricultural University) ;
  • Liu, Juxiong (College of Veterinary Medicine, Jilin University) ;
  • Liu, Guowen (College of Veterinary Medicine, Jilin University) ;
  • Han, Wenyu (College of Veterinary Medicine, Jilin University) ;
  • Wang, Yuping (College of Animal Science, Jilin University) ;
  • Lei, Liancheng (College of Veterinary Medicine, Jilin University)
  • Received : 2015.12.22
  • Accepted : 2016.03.08
  • Published : 2016.05.31

Abstract

During the lactation cycle of the bovine mammary gland, autophagy is induced in bovine mammary epithelial cells (BMECs) as a cellular homeostasis and survival mechanism. Interferon gamma ($IFN-{\gamma}$) is an important antiproliferative and apoptogenic factor that has been shown to induce autophagy in multiple cell lines in vitro. However, it remains unclear whether $IFN-{\gamma}$ can induce autophagy and whether autophagy affects milk synthesis in BMECs. To understand whether $IFN-{\gamma}$ affects milk synthesis, we isolated and purified primary BMECs and investigated the effect of $IFN-{\gamma}$ on milk synthesis in primary BMECs in vitro. The results showed that $IFN-{\gamma}$ significantly inhibits milk synthesis and that autophagy was clearly induced in primary BMECs in vitro within 24 h. Interestingly, autophagy was observed following $IFN-{\gamma}$ treatment, and the inhibition of autophagy can improve milk protein and milk fat synthesis. Conversely, upregulation of autophagy decreased milk synthesis. Furthermore, mechanistic analysis confirmed that $IFN-{\gamma}$ mediated autophagy by depleting arginine and inhibiting the general control nonderepressible-2 kinase (GCN2)/eukaryotic initiation factor $2{\alpha}$ ($eIF2{\alpha}$) signaling pathway in BMECs. Then, it was found that arginine supplementation could attenuate $IFN-{\gamma}$-induced autophagy and recover milk synthesis to some extent. These findings may not only provide a novel measure for preventing the $IFN-{\gamma}$-induced decrease in milk quality but also a useful therapeutic approach for $IFN-{\gamma}$-associated breast diseases in other animals and humans.

Keywords

autophagy;arginine;BMECs;$IFN-{\gamma}$;milk synthesis

References

  1. Ahmadinejad, N., Movahedinia, S., Movahedinia, S., Holakouie, N.K., and Nedjat, S. (2013). Distribution of breast density in Iranian women and its association with breast cancer risk factors. Iran Red Crescent Med. J. 15, e16615.
  2. Angcajas, A.B., Hirai, N., Kaneshiro, K., Karim, M.R., Horii, Y., Kubota, M., Fujimura, S., and Kadowaki, M. (2014). Diversity of amino acid signaling pathways on autophagy regulation: a novel pathway for arginine. Biochem. Biophys. Res. Commun. 446, 8-14. https://doi.org/10.1016/j.bbrc.2014.01.117
  3. Bian, Y., Lei, Y., Wang, C., Wang, J., Wang, L., Liu, L., Liu, L., Gao, X., and Li, Q. (2015). Epigenetic regulation of miR-29s affects the lactation activity of dairy cow mammary epithelial cells. J. Cell Physiol. 230, 2152-2163. https://doi.org/10.1002/jcp.24944
  4. Bionaz, M., and Loor, J.J. (2011). Gene networks driving bovine mammary protein synthesis during the lactation cycle. Bioinform. Biol. Insights 5, 83-98.
  5. Boehm, U., Klamp, T., Groot, M., and Howard, J.C. (1997). Cellular responses to interferon-gamma. Annu. Rev. Immunol. 15, 749-795. https://doi.org/10.1146/annurev.immunol.15.1.749
  6. Borden, E.C., Sen, G.C., Uze, G., Silverman, R.H., Ransohoff, R.M., Foster, G.R., and Stark, G.R. (2007). Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug Discov. 6, 975-990. https://doi.org/10.1038/nrd2422
  7. Bougarn, S., Cunha, P., Gilbert, F.B., Meurens, F., and Rainard, P. (2011). Technical note: Validation of candidate reference genes for normalization of quantitative PCR in bovine mammary epithelial cells responding to inflammatory stimuli. J. Dairy Sci. 94, 2425-2430. https://doi.org/10.3168/jds.2010-3859
  8. Fougeray, S., Mami, I., Bertho, G., Beaune, P., Thervet, E., and Pallet, N. (2012). Tryptophan depletion and the kinase GCN2 mediate IFN-gamma-induced autophagy. J. Immunol. 189, 2954-2964. https://doi.org/10.4049/jimmunol.1201214
  9. Fredericksen, F., Delgado, F., Cabrera, C., Yanez, A., Gonzalo, C., Villalba, M., and Olavarria, V.H. (2015). The effects of reference genes in qRT-PCR assays for determining the immune response of bovine cells (MDBK) infected with the Bovine Viral Diarrhea Virus 1 (BVDV-1). Gene 569, 95-103. https://doi.org/10.1016/j.gene.2015.05.050
  10. Gajewska, M., Gajkowska, B., and Motyl, T. (2005). Apoptosis and autophagy induced by TGF-B1 in bovine mammary epithelial BME-UV1 cells. J. Physiol. Pharmacol. 56 Suppl 3, 143-157.
  11. Hannigan, A.M., and Gorski, S.M. (2009). Macroautophagy: the key ingredient to a healthy diet? Autophagy 5, 140-151. https://doi.org/10.4161/auto.5.2.7529
  12. Harris, J. (2011). Autophagy and cytokines. Cytokine 56, 140-144. https://doi.org/10.1016/j.cyto.2011.08.022
  13. Hu, H., Wang, J., Bu, D., Wei, H., Zhou, L., Li, F., and Loor, J.J. (2009). In vitro culture and characterization of a mammary epithelial cell line from Chinese Holstein dairy cow. PLoS One 4, e7636. https://doi.org/10.1371/journal.pone.0007636
  14. Kimmelman, A.C. (2011). The dynamic nature of autophagy in cancer. Genes Dev. 25, 1999-2010. https://doi.org/10.1101/gad.17558811
  15. Kroemer, G., Marino, G., and Levine, B. (2010). Autophagy and the integrated stress response. Mol. Cell 40, 280-293. https://doi.org/10.1016/j.molcel.2010.09.023
  16. Lee, H.J., Hinshelwood, R.A., Bouras, T., Gallego-Ortega, D., Valdes-Mora, F., Blazek, K., Visvader, J.E., Clark, S.J., and Ormandy, C.J. (2011). Lineage specific methylation of the Elf5 promoter in mammary epithelial cells. Stem Cells 29, 1611-1619. https://doi.org/10.1002/stem.706
  17. Li, J.X., Zhang, Y., Ma, L.B., Sun, J.H., and Yin, B.Y. (2009). Isolation and culture of bovine mammary epithelial stem cells. J. Vet. Med. Sci. 71, 15-19. https://doi.org/10.1292/jvms.71.15
  18. Mackle T.R., Dwyer D.A., Ingvartsen K.L. Chouinard P.Y., Ross D.A., Bauman D.E. (2000). Effects of insulin and postruminal supply of protein on use of amino acids by the mammary gland for milk protein synthesis. J. Dairy Sci. 83, 93-105. https://doi.org/10.3168/jds.S0022-0302(00)74860-0
  19. Maher, S.G., Romero-Weaver, A.L., Scarzello, A.J., and Gamero, A.M. (2007). Interferon: cellular executioner or white knight? Curr. Med. Chem. 14, 1279-1289. https://doi.org/10.2174/092986707780597907
  20. Marino, G., and Lopez-Otin, C. (2004). Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol. Life. Sci. 61, 1439-1454.
  21. Motyl, T., Gajewska, M., Zarzynska, J., Sobolewska, A., and Gajkowska, B. (2007). Regulation of autophagy in bovine mammary epithelial cells. Autophagy 3, 484-486. https://doi.org/10.4161/auto.4491
  22. Pei, J., Zhao, M., Ye, Z., Gou, H., Wang, J., Yi, L., Dong, X., Liu, W., Luo, Y., Liao, M., and Chen, J. (2014). Autophagy enhances the replication of classical swine fever virus in vitro. Autophagy 10, 93-110. https://doi.org/10.4161/auto.26843
  23. Ravikumar, B., Sarkar, S., Davies, J.E., Futter, M., Garcia-Arencibia, M., Green-Thompson, Z.W., Jimenez-Sanchez, M., Korolchuk, V.I., Lichtenberg, M., and Luo, S., et al. (2010). Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90, 1383-1435. https://doi.org/10.1152/physrev.00030.2009
  24. Rubinsztein, D.C., Marino, G., and Kroemer, G. (2011). Autophagy and aging. Cell 146, 682-695. https://doi.org/10.1016/j.cell.2011.07.030
  25. Schmeisser, H., Fey, S.B., Horowitz, J., Fischer, E.R., Balinsky, C.A., Miyake, K., Bekisz, J., Snow, A.L., and Zoon, K.C. (2013). Type I interferons induce autophagy in certain human cancer cell lines. Autophagy 9, 683-696. https://doi.org/10.4161/auto.23921
  26. Sobolewska, A., Gajewska, M., Zarzynska, J., Gajkowska, B., and Motyl, T. (2009). IGF-I, EGF, and sex steroids regulate autophagy in bovine mammary epithelial cells via the mTOR pathway. Eur. J. Cell Biol. 88, 117-130. https://doi.org/10.1016/j.ejcb.2008.09.004
  27. Sobolewska, A., Motyl, T., and Gajewska, M. (2011). Role and regulation of autophagy in the development of acinar structures formed by bovine BME-UV1 mammary epithelial cells. Eur. J. Cell Biol. 90, 854-864. https://doi.org/10.1016/j.ejcb.2011.06.007
  28. Wu Y. (2013). Effects of different types of diet on plasma endotoxin and immune activation in dairy goats and dairy cows. Chinas Excellent MA Degree P.
  29. Yang, J., Kennelly, J.J., and Baracos, V.E. (2000). Physiological levels of Stat5 DNA binding activity and protein in bovine mammary gland. J. Anim. Sci. 78, 3126-3134. https://doi.org/10.2527/2000.78123126x
  30. Zhou, J., Dong, G., Ao, C., Zhang, S., Qiu, M., Wang, X., Wu, Y., Erdene, K., Jin, L., Lei, C., and Zhang, Z. (2014). Feeding a high-concentrate corn straw diet increased the release of endotoxin in the rumen and pro-inflammatory cytokines in the mammary gland of dairy cows. BMC Vet. Res. 10. https://doi.org/10.1186/s12917-014-0172-0

Cited by

  1. Pexophagy is responsible for 65% of cases of peroxisome biogenesis disorders vol.13, pp.5, 2017, https://doi.org/10.1080/15548627.2017.1291480
  2. Nutrient sensing and metabolic changes after methionine deprivation in primary muscle cells of turbot ( Scophthalmus maximus L.) 2017, https://doi.org/10.1016/j.jnutbio.2017.08.015
  3. Amino acids stimulate glycyl-tRNA synthetase nuclear localization for mammalian target of rapamycin expression in bovine mammary epithelial cells pp.00219541, 2018, https://doi.org/10.1002/jcp.27523
  4. 饲喂玉米秸秆粗饲料可加剧奶牛外周血单核细胞释放炎性细胞因子 vol.19, pp.10, 2018, https://doi.org/10.1631/jzus.B1700571
  5. Halofuginone-induced autophagy suppresses the migration and invasion of MCF-7 cells via regulation of STMN1 and p53 vol.119, pp.5, 2018, https://doi.org/10.1002/jcb.26559
  6. γ 干扰素通过c-Abl/HDAC2 信号通路调节乳腺上 皮细胞恶性生长 vol.20, pp.1, 2019, https://doi.org/10.1631/jzus.B1800211