title: 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.
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-γ) 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-γ can induce autophagy and whether autophagy affects milk synthesis in BMECs. To understand whether IFN-γ affects milk synthesis, we isolated and purified primary BMECs and investigated the effect of IFN-γ on milk synthesis in primary BMECs in vitro. The results showed that IFN-γ significantly inhibits milk synthesis and that autophagy was clearly induced in primary BMECs in vitro within 24 h. Interestingly, autophagy was observed following IFN-γ 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-γ mediated autophagy by depleting arginine and inhibiting the general control nonderepressible-2 kinase (GCN2)/eukaryotic initiation factor 2α (eIF2α) signaling pathway in BMECs. Then, it was found that arginine supplementation could attenuate IFN-γ-induced autophagy and recover milk synthesis to some extent. These findings may not only provide a novel measure for preventing the IFN-γ-induced decrease in milk quality but also a useful therapeutic approach for IFN-γ-associated breast diseases in other animals and humans.
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Xia
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Yanyi
authors.initials: Y
authors.lastname: Che
authors.affiliation: College of Animal Science, Jilin University, Changchun, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: College of Animal Science, Jilin University, Changchun, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: College of Animal Science, Inner Mongolian Agricultural University, Hohhot, China.
authors.forename: Changjin
authors.initials: C
authors.lastname: Ao
authors.affiliation: College of Animal Science and Technology, China Agricultural University, Beijing, China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Yang
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Juxiong
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Guowen
authors.initials: G
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Han
authors.affiliation: College of Animal Science, Jilin University, Changchun, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Liancheng
authors.initials: L
authors.lastname: Lei
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D019587:Dietary Supplements; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D007774:Lactation / Q000187:drug effects; D008321:Mammary Glands, Animal / Q000166:cytology*; D008894:Milk Proteins / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008894:Milk Proteins; D007371:Interferon-gamma; D001120:Arginine; D017346:Protein Serine-Threonine Kinases
keywords: BMECs; IFN-γ; arginine; autophagy; milk synthesis