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Vitamin D Decreases Respiratory Syncytial Virus Induction of NF-B–Linked Chemokines and Cytokines in Airway Epithelium While Maintaining the Antiviral State

Department of Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242

Epidemiological studies suggest that low vitamin D levels may increase the risk or severity of respiratory viral infections. In this study, we examined the effect of vitamin D on respiratory syncytial virus (RSV)-infected human airway epithelial cells. Airway epithelium converts 25-hydroxyvitamin D₃ (storage form) to 1,25-dihydroxyvitamin D₃ (active form). Active vitamin D, generated locally in tissues, is important for the nonskeletal actions of vitamin D, including its effects on immune responses. We found that vitamin D induces IB, an NF-B inhibitor, in airway epithelium and decreases RSV induction of NF-B–driven genes such as IFN-β and CXCL10. We also found that exposing airway epithelial cells to vitamin D reduced induction of IFN-stimulated proteins with important antiviral activity (e.g., myxovirus resistance A and IFN-stimulated protein of 15 kDa). In contrast to RSV-induced gene expression, vitamin D had no effect on IFN signaling, and isolated IFN induced gene expression. Inhibiting NF-B with an adenovirus vector that expressed a nondegradable form of IB mimicked the effects of vitamin D. When the vitamin D receptor was silenced with small interfering RNA, the vitamin D effects were abolished. Most importantly we found that, despite inducing IB and dampening chemokines and IFN-β, there was no increase in viral mRNA or protein or in viral replication. We conclude that vitamin D decreases the inflammatory response to viral infections in airway epithelium without jeopardizing viral clearance. This suggests that adequate vitamin D levels would contribute to reduced inflammation and less severe disease in RSV-infected individuals.

Address correspondence and reprint requests to Dr. Sif Hansdottir, University of Iowa Hospitals and Clinics, Division of Pulmonary and Critical Care, 200 Hawkins Drive, C323GH, Iowa City, IA 52242-1081. E-mail address: sif-hansdottir{at}uiowa.edu

This work was supported by National Institutes of Health Grants KL2 RR024980, R01 HL079901, R01 HL077431, R01 HL073967, and T32 HL007638 and a Veterans Administration Merit Review grant.

Abbreviations used in this paper:

1,25D, 1,25-dihydroxyvitamin D₃; hTBE, human tracheobronchial epithelial; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; ISG15, IFN-stimulated protein of 15 kDa; ISRE, IFN-stimulated response element; MOI, multiplicity of infection; MxA, myxovirus resistance A; QRT-PCR, quantitative real-time PCR; RSV, respiratory syncytial virus; siRNA, small interfering RNA; VDR, vitamin D receptor.

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The JI 2010 184: 533-534. [Full Text]  

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