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


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.


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


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