Dataset Information

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.

Project description:BACKGROUND:Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association. STUDY DESIGN:Case-control study. SETTING & PARTICIPANTS:African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium. FACTOR:Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles. OUTCOMES:SSNS and SRNS. MEASUREMENTS:Direct sequencing for the HLA-DQA1 and APOL1 variants in 115 African American children (65 with SSNS and 50 with SRNS). Imputation of classic HLA alleles and amino acids was done in 363 South Asian children. RESULTS:The 2 HLA-DQA1 variants were significantly associated with SSNS in African American children (C34Y: P=5.7 × 10-11; OR, 3.53; 95% CI, 2.33-5.42; F41S: P=1.2 × 10-13; OR, 4.08; 95% CI, 2.70-6.28), but not with SRNS (C34Y: P=0.6; F41S: P=0.2). APOL1 high-risk variants were not associated with SSNS (P=0.5) but showed significant associations with SRNS (P=1.04 × 10-7; OR, 4.17; 95% CI, 2.23-7.64). HLA-DQA1*0201, HLA-DQB1*0201, and HLA-DRB1*0701 were the classic HLA alleles with the most significant associations with SSNS risk. The most significantly associated amino acid positions were HLA-DQ?1 56 and 76 (both P=2.8 × 10-7). Conditional analysis revealed that these variants most likely account for the observed association. LIMITATIONS:Modest sample size and limited statistical power to detect small to moderate effect sizes. Children studied may not be representative of all African American children in the United States. CONCLUSIONS:HLA-DQA1 is a risk locus for SSNS, but not SRNS, in African American children, consistent with its role in SSNS risk in children of European, Asian, and African ancestries. There is little evidence of a significant role for the APOL1 high-risk alleles in childhood SSNS in African American children. Refinement of the HLA-DQA1 association identified the critical classic HLA antigen types and amino acids of the HLA-DQ ?1 molecule.

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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