Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state.
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 IkappaBalpha, an NF-kappaB inhibitor, in airway epithelium and decreases RSV induction of NF-kappaB-driven genes such as IFN-beta 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-kappaB with an adenovirus vector that expressed a nondegradable form of IkappaBalpha 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 IkappaBalpha and dampening chemokines and IFN-beta, 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.
Hansdottir
Sif
S
Department of Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242-1081, USA. sif-hansdottir@uiowa.edu
Monick
Martha M
MM
Lovan
Nina
N
Powers
Linda
L
Gerke
Alicia
A
Hunninghake
Gary W
GW
D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000235:genetics; D007109:Immunity; D007249:Inflammation / Q000188:drug therapy; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014807:Vitamin D / Q000494:pharmacology*
D018925:Chemokines; D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D014807:Vitamin D