| Vitamin D is primarily known for its role in bone health, however recently vitamin D has been identified as a potent immunomodulator. Most research studying the effects of vitamin D on immune properties have focused on immune cells. Few have evaluated how vitamin D affects the immune functions of barrier epithelial cells, such as human mammary epithelial (HME) cells, that are exposed to pathogens both locally and systemically. The goals of the studies described in this thesis were to comprehensively and mechanistically evaluate the immune effects of vitamin D metabolites, 1&agr;,25-dihydroxyvitamin D (1,25D) and 25-hydroxyvitamin D (25D), on HME cells. Genomic profiling by microarray identified a cohort of immune genes that were significantly regulated by 1,25D in HME cells including CD14. CD14 is a pattern recognition receptor that binds lipopolysaccharide, a component of gram-negative bacteria.;Mechanistic approaches were used to define the relationship between vitamin D and CD14 in HME cells. The central hypothesis tested by these studies is that vitamin D alters the inflammatory environment of the mammary gland by stimulating the secretion of soluble CD14 (sCD14) from human mammary epithelial cells through the VDR. The following specific aims were completed to test this hypothesis: 1. To profile the global genomic effects of 1,25D on immune gene expression 2. To characterize the effect of vitamin D on the isoforms of CD14 3. To define the role of the vitamin D receptor in the induction of CD14 by vitamin D 4. To determine the functionality of vitamin D-induced sCD14..;Overall, these studies demonstrated that vitamin D markedly affects immune gene expression in both normal and transformed mammary cells. In the HME cell line, vitamin D metabolites induce the synthesis and secretion of CD14 through both nuclear and membrane VDR pathways. The data support a model in which vitamin D primes HME cells to communicate with tissue immune cells to maintain the immune environment of the mammary gland and facilitate responses to systemic and external signals. The findings from this work have enhanced our understanding of the doseresponse relationship between vitamin D metabolites and immune responses in barrier mammary epithelial cells. |
