Down-regulation of IL-8 by high-dose vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up-regulation of DUSP1.
Br J Pharmacol
; 172(19): 4757-71, 2015 Oct.
Article
in En
| MEDLINE
| ID: mdl-26178144
ABSTRACT
BACKGROUND AND PURPOSE:
There is current interest in vitamin D as a potential anti-inflammatory treatment for chronic inflammatory lung disease, including cystic fibrosis (CF). Vitamin D transcriptionally up-regulates the anti-inflammatory gene DUSP1, which partly controls production of the inflammatory chemokine IL-8. IL-8 is overabundant in CF airways, potentially due to hyperinflammatory responses of CF macrophages. We tested the ability of vitamin D metabolites to down-regulate IL-8 production in CF macrophages. EXPERIMENTALAPPROACH:
CF and healthy monocyte-derived macrophages (MDM) were treated with two vitamin D metabolites, 25-hydroxyvitamin D3 (25OHD3 ) and 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), or paricalcitol, synthetic analogue of 1,25(OH)2 D3 . 25OHD3 was tested at doses of 25-150 nM, whereas 1,25(OH)2 D3 and paricalcitol at doses of up to 100 nM. IL-8 was stimulated by bacterial virulence factors. As potential anti-inflammatory mechanism of vitamin D metabolites, we assessed up-regulation of DUSP1. KEYRESULTS:
MDM from patients with CF and some healthy donors showed excessive production of stimulated IL-8, highlighting their hyperinflammatory phenotype. Vitamin D metabolites down-regulated stimulated IL-8 only in those hyperinflammatory MDM, and only when used at high doses (>100 nM for 25OHD3 , or >1 nM for 1,25(OH)2 D3 and paricalcitol). The magnitude of IL-8 down-regulation by vitamin D metabolites or paricalcitol was moderate (â¼30% vs. >70% by low-dose dexamethasone). Transcriptional up-regulation of DUSP1 by vitamin D metabolites was seen in all tested MDM, regardless of IL-8 down-regulation. CONCLUSIONS AND IMPLICATIONS Vitamin D metabolites and their analogues moderately down-regulate IL-8 in hyperinflammatory macrophages, including those from CF. This down-regulation appears to go through DUSP1-independent mechanisms.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Vitamin D
/
Calcifediol
/
Ergocalciferols
/
Interleukin-8
/
Cystic Fibrosis
/
Macrophages
Limits:
Adult
/
Humans
Language:
En
Journal:
Br J Pharmacol
Year:
2015
Document type:
Article