Regulation of inflammation by selenium and selenoproteins: impact on eicosanoid biosynthesis.

Uncontrolled inflammation is a contributing factor to many leading causes of human morbidity and mortality including atherosclerosis, cancer and diabetes. Se is an essential nutrient in the mammalian diet that has some anti-inflammatory properties and, at sufficient amounts in the diet, has been shown to be protective in various inflammatory-based disease models. More recently, Se has been shown to alter the expression of eicosanoids that orchestrate the initiation, magnitude and resolution of inflammation. Many of the health benefits of Se are thought to be due to antioxidant and redox-regulating properties of certain selenoproteins. The present review will discuss the existing evidence that supports the concept that optimal Se intake can mitigate dysfunctional inflammatory responses, in part, through the regulation of eicosanoid metabolism. The ability of selenoproteins to alter the biosynthesis of eicosanoids by reducing oxidative stress and/or by modifying redox-regulated signalling pathways also will be discussed. Based on the current literature, however, it is clear that more research is necessary to uncover the specific beneficial mechanisms behind the anti-inflammatory properties of selenoproteins and other Se metabolites, especially as related to eicosanoid biosynthesis. A better understanding of the mechanisms involved in Se-mediated regulation of host inflammatory responses may lead to the development of dietary intervention strategies that take optimal advantage of its biological potency.

Enhanced n-3 phospholipid content reduces inflammatory responses in bovine endothelial cells.

Uncontrolled inflammation contributes to the increased incidence and severity of infectious diseases in periparturient dairy cattle. The objective of this study was to determine if increasing n-3 fatty acid (FA) content and altering the profile of vasoactive eicosanoids could attenuate endothelial cell inflammatory responses. Bovine aortic endothelial cells (BAEC) were cultured with free FA mixtures that mimic the plasma NEFA composition during the first week of lactation of dairy cows or with a free FA mixture supplemented with a higher proportion of n-3 FA, including eicosapentaenoic and docosahexaenoic acids. The effects of increasing the docosahexaenoic and eicosapentaenoic acid content of BAEC on the expression of proinflammatory mediators and eicosanoid biosynthesis was assessed. Culturing BAEC with enriched concentrations of n-3 FA decreased the expression of proinflammatory cytokines, adhesion molecules, and reactive oxygen species with a concomitant increase in the biosynthesis of proresolving eicosanoids, including resolvins, protectins, and lipoxins. This study showed for the first time that increasing the n-3 FA content of endothelial cell phospholipids could alter the expression of eicosanoids and control the magnitude of inflammatory responses. Future studies are necessary to elucidate the mechanisms by which resolvins, protectins, and lipoxins may modify endothelial inflammatory pathways necessary to reduce the severity and duration of disease in periparturient cows.

Nonesterified fatty acids modify inflammatory response and eicosanoid biosynthesis in bovine endothelial cells.

Intense lipid mobilization during the transition period in dairy cows is associated with increased disease susceptibility. The potential impact of altered plasma nonesterified fatty acids (NEFA) concentrations and composition on host inflammatory responses that may contribute to disease incidence and severity are not known. The objective of this study was to evaluate if increased NEFA concentrations could modify vascular inflammatory responses in vitro by changing the expression of important inflammatory mediators that are important in the pathogenesis of infectious diseases of transition cows such as mastitis and metritis. Bovine aortic endothelial cells (BAEC) were cultured with different concentrations of a NEFA mixture that reflected the plasma NEFA composition during different stages of lactation. The expression of cytokines, adhesion molecules, and eicosanoids were measured to assess changes in BAEC inflammatory phenotype. Addition of NEFA mixtures altered the fatty acid profile of BAEC by increasing the concentration of stearic acid (C18:0) and decreasing the content of arachidonic acid (C20:4n6c) and other long-chain polyunsaturated fatty acids in the phospholipid fraction. A significant increase also occurred in mRNA expression of cytokine and adhesion molecules that are associated with increased inflammatory responses during the transition period. Expression of cyclooxygenase 2, an important enzyme associated with eicosanoid biosynthesis, was increased in a NEFA concentration-dependent manner. The production of linoleic acid-derived eicosanoids 9- and 13-hydroxyoctadecadienoic acids also was increased significantly after treatment with NEFA mixtures. This research described for the first time specific changes in vascular inflammatory response during in vitro exposure to NEFA mixtures that mimic the composition and concentration found in cows during the transition period. These findings could explain, in part, alterations in inflammatory responses observed during intense lipid mobilization stages such as in the transition period of dairy cows. Future studies should analyze specific mechanisms by which high NEFA concentrations induce a vascular proinflammatory phenotype including the effect of 9 and 13-hydroxyoctadecadienoic acids and other lipid mediators.

Changes in glucose transporter expression in monocytes of periparturient dairy cows.

The transition period of dairy cows is characterized by dramatic changes in metabolism and immune cell function that contributes to increased susceptibility to several economically important diseases. Monocyte and macrophage populations increase in blood and tissues of cows during the transition period and have enhanced inflammatory responses that may contribute to increased severity of disease. Glucose is a major energy source for activated monocytes and glucose uptake is facilitated by glucose transporters (GLUT). The objective of this study was to determine how bovine monocyte GLUT expression changes during lactogenesis and in response to proinflammatory stimulation. Blood samples were collected from 10 dairy cows approximately 5 wk before calving and during the first week of lactation. Monocytes were isolated from total peripheral blood mononuclear cells, and expression of GLUT1, GLUT3, and GLUT4 isoforms was assessed in resting cells and following endotoxin stimulation. In general, the onset of lactation served to decrease overall GLUT expression. Gene and protein expression of GLUT1 was significantly decreased after parturition, and GLUT3 and GLUT4 cell surface expression was also significantly decreased postcalving. Endotoxin stimulation, however, increased gene expression of GLUT3 and GLUT4, and gene expression for all GLUT isoforms was positively correlated to production of tumor necrosis factor-α. This study identified, for the first time, the presence of GLUT isoforms in bovine monocytes. Alterations in monocyte GLUT expression at the onset of lactation warrant further investigation to ascertain how changes in glucose uptake may contribute to periparturient inflammatory dysfunction.

Glucose transporter and hypoxia-associated gene expression in the mammary gland of transition dairy cattle.

Glucose is an important energy substrate, especially needed by dairy cows postpartum to support the onset of lactation. The prioritization and regulation of glucose uptake is accomplished, in part, by changes in expression of cellular glucose transport molecules (GLUT) within the mammary gland. The objectives of this study were to (1) evaluate the expression and cell-type specific localization of GLUT and hypoxia-associated genes that may regulate GLUT expression over the transition period and through lactation in bovine mammary tissue and (2) determine functionality of GLUT on primary bovine mammary endothelial cells (BMEC). Mammary tissue biopsies were taken from cows at 15 d before calving and again at 1, 15, 30, 60, 120, and 240 d post-parturition for quantitative real-time PCR analysis of GLUT and hypoxia-associated genes. Additional mammary tissue samples were used to localize GLUT within the cells of the lobulo-alveolar system via fluorescence microscopy. Cultures of primary bovine mammary endothelial cells were used to confirm the functionality of GLUT with a fluorescent glucose analog uptake assay. Significant increases in GLUT1 gene expression were observed during early lactation, whereas both GLUT3 and GLUT4 gene expression increased during late lactation. The gene expression for 2 receptors of vascular endothelial growth factor increased significantly during early lactation and remained increased throughout lactation when compared with gene expression during the transition period. All GLUT were detected on cultured BMEC and were capable of internalizing glucose through GLUT-mediated mechanisms. These data suggest mammary vascular tissues express GLUT during lactation and BMEC express functional glucose transporters. A better understanding of glucose uptake at the endothelial level may prove to be critical to improve glucose absorption from the blood for utilization by mammary epithelial cells.