Abstract
Inflammation in the mammary gland (mastitis) is the most common disease in dairy herds worldwide, often caused by the pathogens Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Little is known about the effects of mastitis on drug transporters and the impact on transporter-mediated excretion of drugs into milk. We used murine mammary epithelial HC11 cells, after lactogenic differentiation into a secreting phenotype, and studied gene expressions of ABC- and SLC- transporters after treatment of cells with S. aureus and lipopolysaccharide, an endotoxin secreted by E. coli. The studied transporters were Bcrp, Mdr1, Mrp1, Oatp1a5, Octn1 and Oct1. In addition, Csn2, the gene encoding β-casein, was analyzed. As biomarkers of the inflammatory response, gene expressions of the cytokines Il6 and Tnfα and the chemokine Cxcl2 were determined. Our results show that S. aureus and LPS treatment of cells, at non-cytotoxic concentrations, induced an up-regulation of Mdr1 and of the inflammatory biomarkers, except that Tnfα was not affected by lipopolysaccharide. By simple regression analysis we could demonstrate statistically significant positive correlations between each of the transporters with each of the inflammatory biomarkers in cells treated with S. aureus. The coefficients of determination (R2) were 0.7–0.9 for all but one correlation. After treatment of cells with lipopolysaccharide, statistically significant correlations were only found between Mdr1 and the two parameters Cxcl2 and Il6. The expression of Csn2 was up-regulated in cells treated with S. aureus, indicating that the secretory function of the cells was not impaired. The strong correlation in gene expressions between transporters and inflammatory biomarkers may suggest a co-regulation and that the transporters have a role in the transport of cytokines and chemokines. Our results demonstrate that transporters in mammary cells can be affected by infection, which may have an impact on transport of essential compounds and contaminants into milk.
Highlights
Transporters are membrane proteins responsible for mediating in- and efflux transport of endogenous substrates, numerous drugs and other chemicals. [1,2,3,4,5]
HC11 cells were treated with S. aureus at concentrations of 1x106 and 1x108 colony forming units (CFU)/ml and expressions of genes encoding inflammatory biomarkers and β-casein and drug transporters doi:10.1371/journal.pone.0161346.g004
Little is known about the effect of inflammation in the mammary gland on the expression of drug transporters
Summary
Transporters are membrane proteins responsible for mediating in- and efflux transport of endogenous substrates, numerous drugs and other chemicals. [1,2,3,4,5]. ATP-binding cassette (ABC-) and Solute Carrier (SLC-) superfamilies are the two major classes of transporters Individual members of these superfamilies, such as BCRP, MDR1, MRP1, OATP1A2 (the human orthologue of the mouse Oatp1a5), OCTN1 and OCT1 are expressed in apical and basolateral membranes of epithelial cells in the mammary gland with differential expression during the pregnancy-lactation cycle, as reported in rodents, cows and humans [6,7,8,9]. Mastitis is the most common disease in dairy herds worldwide with multifactorial aetiology, including bacterial pathogens causing local pain and reduced milk synthesis [16, 17]. Both duration and severity of mastitis have been suggested to depend on interactions between inflammatory stimuli and the host immune response [18, 19]. Lipopolysaccharide (LPS) is an endotoxin, which is secreted by gram negative bacteria such as E. coli [21]
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