Abstract
The role of vitamin D3 in modulating immune responses has been well-established for over two decades; however, its specific functions have not been extensively detailed in cattle, particularly cattle in different stages of infection with Mycobacterium avium subspecies paratuberculosis (MAP). Consistent with previous work in our lab, the present study showed that infected cattle in the clinical stage of disease have reduced serum 25-hydroxyvitamin D3 [25(OH)D3]. Additionally, effects of vitamin D3 on peripheral blood mononuclear cells (PBMCs) from naturally infected dairy cattle in subclinical (n = 8) or clinical (n = 8) stages of infection were compared to non-infected control cows (n = 8). Briefly, PBMCs were isolated and cultured in vitro with 4 ng/ml 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or 100 ng/ml 25(OH)D3. Treatment with 1,25(OH)2D3 resulted in decreased secretion for some pro-inflammatory cytokines in clinical animals, including IL-1β, IL-6, and IFN-γ. Similar responses for IL-1β and IL-6 were noted with the addition of 25(OH)D3. Additionally, pro-inflammatory cytokine gene expression tended to be upregulated in PBMCs from clinical animals after treatment with 1,25(OH)2D3. In contrast, PBMCs from clinical animals treated with 25(OH)D3 showed downregulation of pro-inflammatory cytokine gene expression, although only significant for IL1B. Following 25(OH)D3 treatment, clinical animals showed significant reduction in CD4+CD25+ T cells. CYP27B1 gene expression was notably decreased in clinical and control animals following 25(OH)D3 treatment but increased in subclinical cows. 1,25(OH)2D3 treatment reduced CYP24A1 gene expression in all groups, while 25(OH)D3 treatment only significantly reduced expression for control cows. Lastly, serum 25(OH)D3 levels were significantly lower in clinical animals. Taken together, these data show vitamin D3 modulates cytokine signaling in cattle at different stages of MAP infection and, therefore, may have implications on disease progression.
Highlights
Vitamin D3 has classically been acknowledged for its role in calcium regulation and bone homeostasis [1]; more recent studies have revealed its role in regulating innate and adaptive immune responses to infectious pathogens [2]
Stimulation with a whole-cell sonicate of Mycobacterium avium subspecies paratuberculosis (MAP) (MPS) increased cytokine secretion by peripheral blood mononuclear cells (PBMCs) in infected cows for IL-10, IL-17A, IFN-γ, and TNF-α compared to non-infected control cows (Figure 2)
Treatment of PBMC cultures with 4 ng/μl 1,25(OH)2D3 for 24 h resulted in significant decreases in pro-inflammatory cytokines IL-1β (Figure 2A; P < 0.05), IL-6 (Figure 2B; P < 0.01), and IFN-γ (Figure 2E; P < 0.05) for clinically infected animals
Summary
Vitamin D3 has classically been acknowledged for its role in calcium regulation and bone homeostasis [1]; more recent studies have revealed its role in regulating innate and adaptive immune responses to infectious pathogens [2]. The inactive analog, 25-hydroxyvitamin D3 [25(OH)D3], can be commonly found in the circulation bound to its vitamin-D-binding protein. This form can be taken up by host immune cells, including T cells [3] and antigen presenting cells (APCs) [4–6], converted via hydroxylation by 1α-hydroxylase (CYP27B1) to its biologically active analog, 1,25(OH)2D3 [1]. Limited work has been done to provide a solid foundation for the role that vitamin D3 may play in modulating the immune response to infectious pathogens, in cattle. A decrease in antigen-specific IFNγ responses has been observed in peripheral blood mononuclear cells (PBMCs) from Mycobacterium bovis (M. bovis) infected cattle following treatment with 1,25(OH)2D3 [7]. A study on Streptococcus uberis induced acute mastitis showed 25(OH)D3 reduced both the mammary gland bacterial load and clinical symptoms following treatment of the infected mammary tissue with 100 μg 25(OH)D3 after each milking [8]
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