Vitamin D Receptor Inhibits Nuclear Factor κB Activation by Interacting with IκB Kinase β Protein

Chen, Yunzi; Zhang, Jing; Ge, Xin; Du, Jie; Deb, Dilip K.; Li, Yan Chun

doi:10.1074/jbc.m113.467670

Cited by 297 publications

(233 citation statements)

References 34 publications

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“…Reported mechanisms include, among others quenching of NFκB 13 and MAPK 14,15 activation, as well as interference with macrophage activation 16 or the Ang-2-Tie-2-MLC kinase cascade. 17 Using the AAA as a clinical example of comprehensive vascular inflammation, 8,9 we show that the effects of VDR activation through the vitamin D analog paricalcitol are restricted, and include an effect on the aneurysm wall T-helper (CD4+) cell content and its associated cytokines, as well as an effect on the expression of the cysteine proteases cathepsins K and L. Thẽ 75% reductions in both T-helper cell content and in the T-helper cell-related cytokines IL-2, 4, and 10 suggest that the reduction in cytokine expression primarily reflects a reduction of aortic wall cell content rather than an effect on cell activation.…”

Section: Discussionmentioning

confidence: 99%

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

Nieuwland

Kokje

Koning

et al. 2016

Laboratory Investigation

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In vitro and in vivo studies attribute potent immune regulatory properties to the vitamin D receptor (VDR). Yet, it is unclear to what extend these observations translate to the clinical context of (vascular) inflammation. This clinical study evaluates the potential of a VDR agonist to quench vascular inflammation. Patients scheduled for open abdominal aneurysm repair received paricalcitol 1 μg daily during 2-4 weeks before repair. Results were compared with matched controls. Evaluation in a parallel group showed that AAA patients are vitamin D insufficient (median plasma vitamin D: 43 (30-62 (IQR)) nmol/l). Aneurysm wall samples were collected during surgery, and the inflammatory footprint was studied. The brief paricalcitol intervention resulted in a selective 73% reduction in CD4+ T-helper cell content (Po0.024 ) and a parallel 35% reduction in T-cell (CD3+) content (Po0.032). On the mRNA level, paricalcitol reduced expression of T-cell-associated cytokines IL-2, 4, and 10 (Po0.019). No effect was found on other inflammatory mediators. On the protease level, selective effects were found for cathepsin K (Po0.036) and L (Po0.005). Collectively, these effects converge at the level of calcineurin activity. An effect of the VDR agonist on calcineurin activity was confirmed in a mixed lymphocyte reaction. In conclusion, brief course of the VDR agonist paricalcitol has profound effects on local inflammation via reduced T-cell activation. The antiinflammatory potential of VDR activation in vitamin D insufficient patients is highly selective and appears to be mediated by an effect on calcineurin-mediated responses.

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Section: Discussionmentioning

confidence: 99%

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

Nieuwland

Kokje

Koning

et al. 2016

Laboratory Investigation

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“…For instance, paricalcitol treatment had suppressed COX-2 and NF-kB expression in colon, leukemic, and gastric cancer cells (10,44), and attenuated VEGF in renal diseases (45). In a constant line, vitamin D has intrinsically shown to inhibit NF-kB activity, reduce NF-kB protein levels, and downregulate a variety of NF-kB target genes in a variety of inflammatory and cancer cell types (46,47). Mechanistically, activation of VDR by vitamin D or its analogues results in VDR/IkB kinase beta protein (IKKb) physical interaction and stimulation/stabilization of the NF-kB inhibitory protein a (IkBa), all of which are responsible for blocking NF-kB binding to DNA and inhibition of its canonical activation pathway (47).…”

Section: Discussionmentioning

confidence: 99%

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

El-Shemi

Refaat

Kensara

et al. 2016

Cancer Prevention Research

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Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), whereas paricalcitol (2.5 mg/kg/day; 3 days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, b-catenin, DKK-1, CDNK-1A, NF-kB, and COX-2 genes, and ELISA was used to quantify the protein levels of b-catenin, COX-2, HSP90, and VEGF. IHC was additionally used to measure b-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, b-catenin, NF-kB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. Ó2016 AACR.

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“…Selanjutnya kemampuan vitamin D yang dimungkinkan dapat mempengaruhi proses penurunan kadar NF-K lainnya adalah melalui jalur vitamin D receptor (VDR). Melalui VDR, vitamin D akan mempengaruhi Inhibitor of NF-K (IKKB) sehingga terjadi hambatan aktivasi NF-K [29].…”

Section: Kadar Nf-k Hewan Cobaunclassified

“…Pada tahap berikutnya interaksi antara VDR dan IKKB akan menghambat pembentukan IKB Kinase (IKK) yang akan menghasilkan feedback penurunan fosforilasi IKKB [29]. Penurunan fosforilasi akan membatalkan IKK dan kembali akan menurukan fosforilasi [30].…”

Section: Kadar Nf-k Hewan Cobaunclassified

Kadar NF- Kβ Pankreas Tikus Model Type 2 Diabetes Mellitus dengan Pemberian Tepung Susu Sapi

Nugroho¹,

Ginting

Diana

2015

IJHN

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AbstrakType 2 Diabetes Mellitus dihubungkan dengan kerusakan sel pankreas yang mempengaruhi jumlah dan fungsi insulin penderitanya. NF-K merupakan golongan protein dalam faktor transkripsi yang diduga memiliki peran penting dalam pro-apoptosis sel pankreas. NF-K merupakan pemicu pro-dan anti-apotosis sel beta pankreas dengan kecenderungan proapoptosis lebih besar dibandingkan peran anti-apoptosisnya. Vitamin D dari susu sapi bubuk adalah vitamin dengan kemampuan menghambat aktifitas NF-Kβ, melalui proses perbaikan sensitivitas dan produksi insulin, serta peningkatan pertahanan sel pankreas. Penelitian ini bertujuan untuk mengukur kekuatan efek pemberian susu sapi bubuk terhadap penurunan NF-K pankreas tikus model type 2 diabetes. Selama 90 hari penelitian, tikus dibagi menjadi 5 kelompok, terdiri dari 2 kelompok kontrol (negative = non-diabetic rat dan positive = diabetic rat) dan 3 kelompok perlakuan (P1, P2 dan P3) dengan dosis pemberian tepung susu sapi adalah 0,9 g/hr, 1,8 g/hr dan 2,7 g/hr. Pada akhir penelitian kadar NF-K pankreas tikus diukur menggunakan metode Elisa. Hasil uji Mann Whitney U terhadap kadar NF-K kelompok perlakuan dibandingkan kontrol positif menunjukkan tidak ditemukan perbedaan (p value = 1,000; 0,086; 0,248). Efek penurunan kadar NF-K yang diharapkan dari pemberian susu sapi bubuk pada keadaan diabetes tidak terbukti. Sehingga disimpulkan pemberian susu sapi bubuk tidak dapat digunakan untuk mencegah kerusakan sel pankreas melalui mekanisme penurunan NF-K.

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Vitamin D Receptor Inhibits Nuclear Factor κB Activation by Interacting with IκB Kinase β Protein

Cited by 297 publications

References 34 publications

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

Kadar NF- Kβ Pankreas Tikus Model Type 2 Diabetes Mellitus dengan Pemberian Tepung Susu Sapi

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