IFN-γ Activates the TLR4-CCL5 Signaling Through Reducing Arginine Level, Leading to Enhanced Susceptibility of Bovine Mammary Epithelial Cells to Staphylococcus aureus.

Dairy cow mastitis is a common bacterial infectious disease which seriously threatens the development of the dairy cow industry. Previous studies have found that increased IFN-γ expression in dairy cows makes dairy cows more susceptible to mastitis, but the underlying mechanism is still not known. In this study, we utilized the in vitro bovine mammary epithelial cells (BMECs) model to explore the molecular mechanism via transcriptome sequencing technology, immunofluorescence, and Western blotting. It was found that IFN-γ promoted the adhesion and invasion of Staphylococcus aureus to BMECs through increasing the expression of TLR4-mediated CCL5 in BMECs. IFN-γ increased the activity of arginase II and reduced the level of arginine in cells, while the addition of arginine inhibited the expression of TLR4 and CCL5. An invasion experiment in mice further validated that IFN-γ treatment significantly increased the bacterial load in mammary glands and blood. However, the colonization and diffusion of S. aureus were interestingly decreased after Arg supplement. These data reveal that increased IFN-γ reduces arginine levels and activates TLR4-CCL5 signaling, leading to enhanced susceptibility of BMECs to S. aureus. Our findings are helpful to understand the pathogenesis of dairy cow mastitis and provide a theoretical basis for improvement of mastitis resistance in dairy cows.

Arginine inhibits the malignant transformation induced by interferon-gamma through the NF-κB-GCN2/eIF2α signaling pathway in mammary epithelial cells in vitro and in vivo.

Breast cancer is the most common female malignant tumors in the world. It seriously affects women's physical and mental health and the leading cause of cancer death among women. Our previous study demonstrated that diet-derived IFN-γ promoted the malignant transformation of primary bovine mammary epithelial cells by accelerating arginine depletion. The current study aimed to explore whether arginine addition could inhibit the degree of malignant transformation and its molecular mechanism. The results indicate that arginine addition could alleviate the malignant transformation of mammary epithelial cells induced by IFN-γ, including reducing cell proliferation, cell migration and colony formation, through the NF-κB-GCN2/eIF2α pathway. The in vivo experiments also consistently confirmed that arginine supplementation could significantly inhibit tumor growth in tumor-bearing mice. Furthermore, the investigation of the clinical data also revealed that the plasma or tissue from human breast cancer patients owned lower arginine level and higher IFN-γ level than that from patients with benign breast disease, showing IFN-γ may be a potential control target. Our findings demonstrate that arginine supplement could antagonize the malignant transformation of mammary epithelial cells induced by IFN-γ (nutritionally induced) both in vitro and in vivo, and IFN-γ was higher in breast cancer women. This might provide a novel strategy for the prevention and treatment of breast cancer regarding to nutrition.