Vitamin D and Immunomodulation in Bronchial Asthma

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Agrawal, Tanupriya
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Asthma is one of the most common chronic inflammatory diseases of the airways. The chronic inflammation is associated with airway hyperresponsiveness (AHR), airway obstruction and airway remodeling. In asthmatics the airway epithelium produces increased amounts of proinflammatory cytokines including TNF-α (Tumour Necrosis Factor-α), IL-1(Interleukin-1), IL-6(Interleukin-6), IL-8(Interleukin-8),and Transforming Growth Factor-β (TGF-β). Airway Smooth Muscle Cells (ASMCs) when activated in an antigen sensitized state, behave in an autocrine and paracrine manner by producing and responding to mediators such as TNF-α, IL-1β, IL-5, IL-6, IL-8, IL-17, GM-CSF (Granulocyte macrophage colony-stimulating factor), TGF-β, RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted), Eotaxin, MCP- 1,2,3 (monocyte chemotactic protein). NF-κB (nuclear factor kappa-light-chainenhancer of activated B cells) is a key transcriptional factor that regulates and coordinates the expression of various inflammatory genes and inflammatory mediators. The p50 and RelA subunits of NF-κB are translocated to the nucleus by importin α3 and importin α4. The potent immunomodulatory role of Vitamin D in both innate and adaptive immunity has recently been appreciated. Calcitriol exerts its action through the Vitamin D receptor (VDR), which is a high affinity nuclear receptor. VDR functions as a transcription factor that alters the transcription of target genes involved in a wide spectrum of biological responses. The effects of vitamin D on the immune system make it a potent immunoregulator and immunomodulator. Individuals with a vitamin D deficiency are predisposed to asthma and allergies in the presence of other environmental stimuli. Lower serum vitamin D levels are associated with airway hyperresponsiveness and increased asthma severity. The central hypothesis of these studies is that vitamin D reduces allergic airway inflammation and airway hyperresponsiveness by inhibiting the transcription and translation of importin α3 and attenuating the migration of NF-κB to the nucleus of airway cells. Cultured human bronchial smooth muscle cells (HBSMCs) were serum starved for 24 hrs and then stimulated with calcitriol in the presence and absence of cytokines, TNF-α, IL-1β, and/or IL-10 for 24 hrs. The mRNA transcripts and protein expression of importin α3 and α4 were analyzed using qPCR and immunoblotting respectively. The nuclear proteins were extracted and RelA expression was also analyzed by immunoblotting. In vivo studies included female BALB/c mice that were fed either a vitamin D-deficient or 2,000 IU/kg or 10,000 IU/kg of vitamin D-supplemented diet. Allergic airway inflammation in mice was induced by OVA- sensitization and challenge. AHR to methacholine was measured using invasive and non- invasive methods . Bronchoalveolar lavage fluid (BALF), blood, and lungs were collected at sacrifice. In HBSMCs, calcitriol significantly decreased mRNA and protein expression of importin α3 and protein expression of NF-кBp65 (RelA) in the nucleus. Calcitriol attenuated the effects of TNF-α and IL-1β and upregulated mRNA and protein expression of importin α3. IL-10 significantly decreased the TNF-α induced expression of importin α3 and this effect was further potentiated by calcitriol. Vitamin D-deficient OVA-sensitized and challenged mice exhibited exaggerated response to methacholine, with increased airway inflammation compared to vitamin D sufficient and supplemented OVA-sensitized and challenged mice. Interestingly, the OVA-sensitized and challenged supplemented group had reduced allergic airway inflammation compared to vitamin D sufficient OVA-sensitized and challenged mice but not to the level of PBS control animals. Similarly, the levels of cytokines IL-5, IL-6, IL- 13, IL-17 and TNF-α were higher in the vitamin D-deficient group of OVA-sensitized mice. On the contrary, high serum levels of vitamin D in OVA-sensitized mice were associated with lower levels of the cytokines, although cytokine levels were significantly higher than those observed in control PBS mice of vitamin D-deficient group. Vitamin D did not alter the levels of IL-4, RANTES or IP-10 in OVA-sensitized group. Serum vitamin D levels positively correlated to the levels of T-regulatory cells in the PBS control group; OVA-sensitization decreased the number of T-regulatory cells. This was more marked in the vitamin D deficient group. Similar trend was observed with the IL- 10 levels. Vitamin D deficiency was associated with increased expression of TNF-α and importin α3, and decreased expression of VDR. Supplementation with vitamin D reduced the levels of TNF-α and importin α3, and increased expression of VDR. We postulate that increased VDR activation due to high serum vitamin D levels (25(OH) D) may be responsible for reducing allergic airway inflammation. The findings in this study suggest a therapeutic role for vitamin D in allergic asthma. These results show that vitamin D supplementation alleviates allergic airway inflammation but does not completely reverse the inflammation. We support the practice of vitamin D supplementation as an adjunct to the treatment of asthma.
Creighton University
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