Abstract
Increased levels of long noncoding RNA H19 (H19) have been observed in many inflammatory and organ fibrosis diseases including ulcerative colitis, osteoarthritis, liver fibrosis, renal fibrosis and pulmonary fibrosis. However, the role of H19 in bovine mastitis and mastitis-caused fibrosis is still unclear. In our study, H19 was characterized as a novel regulator of EMT induced by transforming growth factor-β1 (TGF-β1) in bovine mammary alveolar cell-T (MAC-T) cell line. We found that H19 was highly expressed in bovine mastitis tissues and inflammatory MAC-T cells induced by virulence factors of pathogens. TGF-β1 was also highly expressed in inflammatory MAC-T cells, and exogenous TGF-β1 could induce EMT, enhance extracellular matrix protein expression, and upregulate H19 expression in epithelial cells. Stable expression of H19 significantly promotes EMT progression and expression of ECM protein induced by TGF-β1 in MAC-T cells. Furthermore, by using a specific inhibitor of the PI3K/AKT pathway, we demonstrated that TGF-β1 upregulated H19 expression through PI3K/AKT pathway. All these observations imply that the lncRNA H19 modulated TGF-β1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT signaling pathway, which suggests that mammary epithelial cells might be one source for myofibroblasts in vivo in the mammary glands under an inflammatory condition, thereby contributing to mammary gland fibrosis.
Highlights
Bovine mastitis is a common disease that occurs in dairy herds and is caused by changes in metabolism, physiological trauma, and contagious or environmental pathogenic microorganisms (Oviedo-Boyso et al, 2007)
To investigate whether H19 mediates the process of bovine mastitis, we first examined the expression of H19 in normal and inflammatory bovine mammary tissue
We found that H19 overexpression enhanced transforming growth factor-β1 (TGF-β1)-induced Epithelial mesenchymal transition (EMT) in mammary alveolar cell-T (MAC-T) cells, indicating that high H19 expression was associated with EMT, which is consistent with the previous observation that transforming growth factor (TGF)-β1 is associated with EMT and inflammation (Franco et al, 2010; Gal et al, 2008; Salgado et al, 2017)
Summary
Bovine mastitis is a common disease that occurs in dairy herds and is caused by changes in metabolism, physiological trauma, and contagious or environmental pathogenic microorganisms (Oviedo-Boyso et al, 2007). Both mastitis and mastitis-caused fibrosis affect the dairy industry by reducing milk production and increasing treatment costs. Epithelial mesenchymal transition (EMT) is the process by which epithelial cells gradually acquire certain characteristics of mesenchymal cells to produce fibroblasts and myofibroblasts (He et al, 2017). It is characterized by morphological changes in epithelial cells from a cobblestone-shape to a spindle-shape and expression changes in some EMT markers, such as decreased E-cadherin and increased vimentin and α-smooth muscle actin (α-SMA) (Thiery, 2002). Transforming growth factor (TGF)-β1 can induce EMT during organ fibrosis and is regarded as a master regulator of EMT progression (Moustakas & Heldin, 2016; Risolino et al, 2014)
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