Degree Type

Dissertation

Date of Award

2010

Degree Name

Doctor of Philosophy

Department

Biochemistry, Biophysics and Molecular Biology

First Advisor

Donald C. Beitz

Second Advisor

John D. Lippolis

Abstract

Vitamin D has predominantly been associated with calcium homeostasis, but recently been associated with several infectious diseases. The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is known to regulate the expression of numerous genes throughout the body. 1,25(OH)2D3 is synthesized from 25-hydroxyvitamin D3 by the enzyme 1α-hydroxylase (1α-OHase; CYP27B1). In the endocrine system, 1α-OHase expression, and subsequently 1,25(OH)2D3 synthesis, is tightly regulated in the kidney in response to calcium homeostasis. 1,25(OH)2D3 produced in the kidney acts systemically to regulate the expression of genes related to calcium homeostasis. In contrast, we have found that bovine monocytes (precursors to macrophages) express 1α-OHase upon activation by toll-like receptor recognition of pathogen associated molecular patterns. Furthermore, we found that 1α-OHase is highly expressed in CD14+ cells (monocytes and macrophages) from peripheral blood mononuclear cell cultures stimulated with a purified protein derivative of Mycobacteria bovis and from the infected mammary glands of cows with mastitis. Production of 1,25(OH)2D3 by 1α-OHase in bovine monocytes up-regulated the expression of the genes for iNOS and the chemokine RANTES in monocytes. Up-regulation of iNOS resulted in increased production of nitric oxide, a molecule that is considered to have several important roles in immune function. In stimulated peripheral blood mononuclear cell cultures, IFN-γ, IL-17A, and IL-17F, pro-inflammatory cytokines associated with T-cells, were down-regulated by 1,25(OH)2D3 that was presumably produced by monocytes. Finally, regulation of gene expression by 1,25(OH)2D3 produced by 1α-OHase in monocytes depended on the concentration of 25(OH)D3. The circulating concentration of 25(OH)D3 is controlled by dietary intake of vitamin D3 and sunlight exposure, so dietary intake of vitamin D3 and sunlight exposure may impact immune function in cattle. Current requirements for vitamin D in cattle are based on the regulation of calcium homeostasis, but those requirements may be inadequate for proper immune function. Therefore, further investigation is needed to determine vitamin D requirements for proper immune function in cattle.

Copyright Owner

Corwin Drew Nelson

Language

en

Date Available

2012-04-30

File Format

application/pdf

File Size

117 pages

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