IDENTIFICATION OF FACTORS ASSOCIATED WITH IMMUNE SUPPRESSION AND MASTITIS
Location: Ruminant Diseases and Immunology Research Unit
Title: Modulation of the Bovine Innate Immune Response by Production of 1alpha,25-Dihydroxyvitamin D3 in Bovine Monocytes
Submitted to: Journal of Dairy Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 30, 2009
Publication Date: March 1, 2010
Citation: Nelson, C.D., Reinhardt, T.A., Thacker, T.C., Beitz, D.C., Lippolis, J.D. 2010. Modulation of the Bovine Innate Immune Response by Production of 1alpha,25-Dihydroxyvitamin D3 in Bovine Monocytes. Journal of Dairy Science. 93(3):1041-1049.
Interpretive Summary: Proper immune function in cattle is critical for the prevention of diseases in cattle that may affect the safety and availability of our meat and dairy products. This study shows that vitamin D is necessary for proper immune function in cattle. Monocytes are a population of immune cells that non-specifically recognize pathogens and are among the first cells to arrive at a site of infection. We show that when monocytes recognize a pathogen they produce an enzyme that converts the inactive form of vitamin D to the active form. We also show that the newly activated vitamin D increases the production of other genes involved in the initiation of the immune response. The concentration of vitamin D in cattle is dependent on supplementation in the diet and exposure to sun. Current recommendations for vitamin D supplementation are largely based on how vitamin D controls calcium availability in cattle. However, the mechanism by which vitamin D regulates the immune response in cattle is distinct from vitamin D regulation of calcium availability in cattle. Therefore, future studies are needed to determine the amount of vitamin D that is necessary to support optimum immune function and overall health in cattle.
In cattle, the kidney has been the only known site for production of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) from 25-hydroxyvitamin D3 25(OH)D3 by 1alpha-hydroxylase (1alpha-OHase). However, recent studies have shown that human monocytes express 1alpha-OHase and produce 1,25(OH)2D3 in response to toll-like receptor (TLR) recognition of bacterial cell wall components. Production of 1,25(OH)2D3 in human monocytes functions to regulate gene expression in an intracrine pathway to improve the antimicrobial activity of monocytes. This is in contrast to the endocrine pathway where 1,25(OH)2D3 is produced by 1alpha-OHase in the kidney and 1,25(OH)2D3 acts systemically to regulate mineral homeostasis. We hypothesized that bovine monocytes could also produce 1,25(OH)2D3 upon activation and 1,25(OH)2D3 would regulate gene expression in monocytes. First, the effects of 1,25(OH)2D3 on bovine monocytes isolated from peripheral blood were tested. Treatment of non-stimulated monocytes with 1,25(OH)2D3 increased 24-hydroxylase (24-OHase) gene expression, but 1,25(OH)2D3 induction of 24-OHase expression was blocked by LPS stimulation. It was also found that 1,25(OH)2D3 increased the gene expression of iNOS and the chemokine RANTES/CCL5 in LPS-stimulated monocytes. Next, the ability of bovine monocytes to express 1alpha-OHase and produce 1,25(OH)2D3 was tested. Activation of monocytes with LPS, tripalmitoylated lipopeptide (Pam3CSK4), or peptidoglycan (PGN) increased 1alpha-OHase gene expression significantly. Addition of 25(OH)D3 to LPS-stimulated monocytes enhanced expression of RANTES and iNOS and production of nitric oxide, showing that activated monocytes can convert 25(OH)D3 to 1,25(OH)2D3. In conclusion, bovine monocytes produce 1,25(OH)2D3 in response to TLR signaling and 1,25(OH)2D3 production in monocytes increases RANTES and iNOS gene expression and nitric oxide production. Evidence from this study suggests that vitamin D status of cattle maybe important for optimal innate immune function due to activation of genes by 1,25(OH)2D3 produced from endogenous 25(OH)D3 in activated monocytes.