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Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma.

ABSTRACT: Vitamin D is known for its anti-inflammatory effects.Vitamin D regulation of responses in patients with steroid-resistant (SR) versus steroid-sensitive (SS) asthma has not been studied.Peripheral blood cells from 11 patients with SR asthma and 8 patients with SS asthma were preincubated with 1,25-dihydroxyvitamin D (1,25[OH]2D [VitD]), followed by dexamethasone (DEX) treatment and LPS stimulation. LPS-induced phosphorylated p38 mitogen-activated protein kinase (p-p38) in monocytes was examined by means of flow cytometry. Mitogen-activated protein kinase phosphatase-1 (MKP-1) mRNA expression, which inhibits p-p38, was analyzed by means of real-time PCR. Glucocorticoid receptor (GR) binding and histone H4 acetylation in the glucocorticoid response element of the MKP-1 promoter in monocytes were analyzed by means of chromatin immunoprecipitation.DEX significantly inhibited LPS-induced p-p38 in monocytes from patients with SS asthma but not those from patients with SR asthma (P < .01). VitD inhibited LPS-induced p-p38 in monocytes from both patient groups (P < .01) but enhanced DEX suppression of LPS-induced p-p38 only in monocytes from patients with SS asthma (P < .01). VitD induced MKP-1 expression and enhanced DEX induction of MKP-1 in both patients with SS asthma and patients with SR asthma. VitD/DEX-induced MKP-1 mRNA levels remained significantly lower in monocytes from patients with SR asthma (P < .05). DEX-stimulated recruitment of GR and histone H4 acetylation at the glucocorticoid response element 4.6 kbp upstream of the MKP-1 gene were significantly lower in monocytes from patients with SR asthma compared with those from patients with SS asthma. VitD pretreatment enhanced DEX-induced GR binding and histone acetylation in monocytes from both patient groups. However, GR binding and histone H4 acetylation remained significantly lower in monocytes from patients with SR asthma.VitD demonstrated anti-inflammatory and corticosteroid-enhancing effects in monocytes of patients with SR asthma and patients with SS asthma. However, the responses to corticosteroids in patients with SR asthma remained significantly lower than those in patients with SS asthma.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4040328 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma.

Zhang Yong Y Leung Donald Y M DY Goleva Elena E

The Journal of allergy and clinical immunology 20140111 6

<h4>Background</h4>Vitamin D is known for its anti-inflammatory effects.<h4>Objective</h4>Vitamin D regulation of responses in patients with steroid-resistant (SR) versus steroid-sensitive (SS) asthma has not been studied.<h4>Methods</h4>Peripheral blood cells from 11 patients with SR asthma and 8 patients with SS asthma were preincubated with 1,25-dihydroxyvitamin D (1,25[OH]2D [VitD]), followed by dexamethasone (DEX) treatment and LPS stimulation. LPS-induced phosphorylated p38 mitogen-activat ...[more]

PMID: 24418482

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Project description:The cause of corticosteroid-resistant (CR) asthma is unknown.We sought to perform gene microarray analyses by using bronchoalveolar lavage (BAL) cells from well-characterized subjects with CR asthma and subject with corticosteroid-sensitive (CS) asthma to elucidate the differential expression of genes that contribute to the development of corticosteroid resistance.The patients were characterized as having CR or CS asthma based on FEV(1) percent predicted improvement after a 1-week course of oral prednisone. Expression of selected gene targets was verified by means of real-time PCR and ELISA.Microarray analyses demonstrated significantly higher levels (>3-fold increase, P < .05) of transcripts for TNF-alpha, IL-1 alpha, IL-1 beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, and CCL20 in BAL cells of subjects with CR asthma. These findings, confirmed by means of RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively activated macrophages, arginase I and CCL24, were decreased. Genes associated with activation of the LPS signaling pathway (early growth response 1, dual-specificity phosphatase 2, molecule possessing ankyrin repeats induced by LPS, and TNF-alpha-induced protein 3) were significantly increased in BAL samples from subjects with CR asthma (P < .05). These patients had significantly higher amounts (1444.0 +/- 457.3 pg/mg total protein) of LPS in BAL fluid than seen in subjects with CS asthma (270.5 +/- 216.0 pg, P < .05), as detected by using the LAL assay and confirmed by means of gas chromatographic/mass spectrometric analysis. Prolonged exposure to LPS induced functional steroid resistance to dexamethasone in normal human monocytes, as demonstrated by persistently increased IL-6 levels in the presence of dexamethasone.Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from subjects with CR asthma suggest that LPS exposure might contribute to CR asthma.

Dataset Information

Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma.

Publications

Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma.

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