Differential effect of vitamin D on NOD2- and TLR-induced cytokines in Crohn's disease

Dionne, Serge; Calderon, Mario R.; White, John H.; Memari, Babak; Elimrani, Ihsan; Adelson, Brandon A.; Piccirillo, Ciriaco A.; Seidman, Ernest G.

doi:10.1038/mi.2014.30

Cited by 21 publications

(16 citation statements)

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“…Many studies have shown that numerous risk genes of CD code for molecules involved in host defense against pathogens, such as nucleotide-binding oligomerization domain 2 ( NOD2 ), ATG16L1 , and those implicated in the T helper type 17 (Th17) pathway[ 38 - 43 ]. Here, we tested the hypothesis that PBMCs of patients with CD, even at the stage of clinical remission, exhibit an altered gene expression profile upon challenge with pathogen-associated molecular patterns (PAMPs) and/or the immunomodulatory hormone vitamin D, which has previously been shown to exert differential effects on the expression of NOD2- and TLR-induced cytokines in the context of CD[ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Underscoring its role in the pathogenesis of CD, vitamin D was shown to be an inductor of NOD2 gene expression[ 25 ]. Using peripheral blood mononuclear cells (PBMCs) and dendritic cells, Dionne et al[ 26 ] showed that 1, 25-vitamin D acts as a modulator of the innate immune system. However, little is known about the effects of vitamin D and the presence of NOD2 mutations on different gene expression levels in CD.…”

Section: Introductionmentioning

confidence: 99%

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NOD2- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn’s disease patients

Schäffler¹,

Rohde²,

Rohde³

et al. 2018

WJG

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AIMTo investigate disease-specific gene expression profiles of peripheral blood mononuclear cells (PBMCs) from Crohn’s disease (CD) patients in clinical remission.METHODSPatients with CD in clinical remission or with very low disease activity according to the Crohn’s disease activity index were genotyped regarding nucleotide-binding oligomerization domain 2 (NOD2), and PBMCs from wild-type (WT)-NOD2 patients, patients with homozygous or heterozygous NOD2 mutations and healthy donors were isolated for further analysis. The cells were cultured with vitamin D, peptidoglycan (PGN) and lipopolysaccharide (LPS) for defined periods of time before RNA was isolated and subjected to microarray analysis using Clariom S assays and quantitative real-time PCR. NOD2- and disease-specific gene expression profiles were evaluated with repeated measure ANOVA by a general linear model.RESULTSEmploying microarray assays, a total of 267 genes were identified that were significantly up- or downregulated in PBMCs of WT-NOD2 patients, compared to healthy donors after challenge with vitamin D and/or a combination of LPS and PGN (P < 0.05; threshold: ≥ 2-fold change). For further analysis by real-time PCR, genes with known impact on inflammation and immunity were selected that fulfilled predefined expression criteria. In a larger cohort of patients and controls, a disease-associated expression pattern, with higher transcript levels in vitamin D-treated PBMCs from patients, was observed for three of these genes, CLEC5A (P < 0.030), lysozyme (LYZ; P < 0.047) and TREM1 (P < 0.023). Six genes were found to be expressed in a NOD2-dependent manner (CD101, P < 0.002; CLEC5A, P < 0.020; CXCL5, P < 0.009; IL-24, P < 0.044; ITGB2, P < 0.041; LYZ, P < 0.042). Interestingly, the highest transcript levels were observed in patients with heterozygous NOD2 mutations.CONCLUSIONOur data identify CLEC5A and LYZ as CD- and NOD2-associated genes of PBMCs and encourage further studies on their pathomechanistic roles.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NOD2- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn’s disease patients

Schäffler¹,

Rohde²,

Rohde³

et al. 2018

WJG

View full text Add to dashboard Cite

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“…The pathophysiology regarding how vitamin D deficiency affects anti‐TNF‐α response requires further clarification. Vitamin D has also been showed to induce expression of the nucleotide‐binding oligomerisation domain (NOD2) gene, a susceptibility gene associated with Crohn's disease, and has been suggested to be a potential immune modulator in vitro . However, further studies clarifying the interaction between vitamin D, NOD2 and disease course are warranted.…”

Section: Discussionmentioning

confidence: 99%

Higher 25‐hydroxyvitamin D levels are associated with greater odds of remission with anti‐tumour necrosis factor‐α medications among patients with inflammatory bowel diseases

Winter

Collins

Cao

et al. 2017

Aliment Pharmacol Ther

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Background Vitamin D has been linked to disease activity among patients with inflammatory bowel diseases (IBD). Prior investigation has also suggested that vitamin D levels may affect duration of therapy with anti-tumor necrosis factor-α (anti-TNF-α) medications among patients with IBD. Aims This study aimed to evaluate the relationship between vitamin D levels and odds of reaching remission while on an anti-TNF-α medication. Methods 521 IBD patients enrolled in the Brigham and Women’s IBD Center database were eligible for inclusion. Patients treated with anti-TNF-α therapy who had vitamin D levels drawn within 6 months prior or 2 weeks after initiation of anti-TNF-α medication and who had reported remission status at 3 months were included. A logistic regression model adjusting for age, gender, IBD diagnosis, anti-TNF-α medication (infliximab versus adalimumab) and first or subsequent anti-TNF-α medication was used to identify the effect of vitamin D level on initial response to anti-TNF-α therapy. Results 173 patients were included in the final analysis. On logistic regression, patients with normal vitamin D levels at the time of anti-TNF-α medication initiation had a 2.64 increased odds of remission at 3 months compared to patients with low vitamin D levels when controlling for age, gender, diagnosis, type of anti-TNF-α medication and first or subsequent anti-TNF-α medication (OR 2.64, 95% CI 1.31–5.32, p 0.0067). Conclusion These findings suggest that vitamin D levels may influence initial response to anti-TNF-α medication and that low vitamin D levels may predispose patients to decreased odds of remission.

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“…Studies by Sadeghi et al and Dickie et al ( 36 , 37 ) both reported that 1,25(OH)D 3 suppressed the expression of TLR proteins and mRNA in human monocytes in a time- and dose-dependent fashion in vitro and reduced the recognition of bacterial specific antigens through monocytes. Another recent study showed that it decreased TLR-induced cytokine production and enhanced cytokine levels in peripheral mononuclear cells and monocyte-derived dendritic cells from CD patients ( 38 ). Our data showed that treating TNBS-induced colitis with 1,25(OH)D 3 could reduce TLR9 expression in the rat colon.…”

Section: Discussionmentioning

confidence: 99%

1,25-hydroxyvitamin D relieves colitis in rats via down-regulation of toll-like receptor 9 expression

et al. 2015

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AimTo investigate the therapeutic and immunoregulatory effects of 1,25-dihydroxyvitamin D (1,25(OH)D3) on 2,4,6-trinitrobenzenesulfonic acid (TNBS) -induced colitis in rats.MethodsExperimental colitis induced by enema administration of TNBS plus ethanol was treated with 5-aminosalicylic acid (5-ASA) and/or 1,25(OH)D3. Disease activity was measured using the disease activation index (DAI), colon macroscopic damage index (CMDI), histological colonic damage score, and myeloperoxidase (MPO) activity. The expression of toll-like receptor 9 (TLR9) in the colon was determined by reverse transcription-polymerase chain reaction and immunohistochemistry.ResultsRats with TNBS-induced colitis had significantly elevated DAI, CMDI, histological colonic damage score, and MPO activity (all P < 0.001) compared to rats without colitis. Treatment with 5-ASA or 1,25(OH)D3 ameliorated colitis by lowering CMDI (P = 0.049, P = 0.040, respectively), histological colonic damage score (P = 0.010, P = 0.005, respectively), and MPO activity (P = 0.0003, P = 0.0013, respectively) compared with the TNBS group. Combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased MPO activity (P = 0.003). 1,25(OH)D3 attenuated colitis without causing hypercalcemia or renal insufficiency. TNBS significantly increased the number of TLR9 positive cells compared to control (P < 0.010), while 5-ASA, 1,25(OH)D3, and combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased it compared to TNBS group (all P < 0.010). In TNBS group a moderate correlation was observed between MPO activity and the number of TLR9-positive cells (r = 0.654, P < 0.001).ConclusionTLR9 expression correlates with the extent of inflammation in TNBS-induced colitis. 1,25(OH)D3 relieves this inflammation possibly by decreasing TLR9 expression.

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Differential effect of vitamin D on NOD2- and TLR-induced cytokines in Crohn's disease

Cited by 21 publications

References 49 publications

NOD2- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn’s disease patients

NOD2- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn’s disease patients

Higher 25‐hydroxyvitamin D levels are associated with greater odds of remission with anti‐tumour necrosis factor‐α medications among patients with inflammatory bowel diseases

1,25-hydroxyvitamin D relieves colitis in rats via down-regulation of toll-like receptor 9 expression

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