scholarly journals TRAF3 Modulation: Novel Mechanism for the Anti-inflammatory Effects of the Vitamin D Receptor Agonist Paricalcitol in Renal Disease

2020 ◽  
Vol 31 (9) ◽  
pp. 2026-2042 ◽  
Author(s):  
Sandra Rayego-Mateos ◽  
Jose Luis Morgado-Pascual ◽  
José Manuel Valdivielso ◽  
Ana Belén Sanz ◽  
Enrique Bosch-Panadero ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Cultured Cells ◽  
Kidney Injury ◽  
Preclinical Model ◽  
Protein Levels ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Injury Models ◽  
Inflammatory Effect

BackgroundCKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood.MethodsModulation of the noncanonical NF-κB2 pathway and its component TNF receptor–associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models.ResultsIn PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-κB2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-κB2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA’s effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-κB2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-κB2–dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol.ConclusionsThese data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-κB2 pathway, identifying a novel mechanism for VDRA’s effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.

scholarly journals P0087TRAF3 MODULATION: A NOVEL MECHANISM OF THE ANTI-INFLAMMATORY EFFECTS OF VITAMIN D RECEPTOR AGONIST PARICALCITOL IN RENAL DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Sandra Rayego-Mateos ◽  
Jose Luis Morgado Pascual ◽  
José M Valdivielso ◽  
Ana Sanz ◽  
Enrique Bosch panadero ◽  
...  
Keyword(s):  
Vitamin D ◽  
Renal Disease ◽  
Vitamin D Receptor ◽  
Renal Damage ◽  
Preclinical Models ◽  
Renal Inflammation ◽  
Protein Levels ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Abstract Background and Aims Tumor necrosis factor receptor-associated factors (TRAFs) are critical signaling adaptors downstream of pro-inflammatory receptors, involved in canonical and non-canonical nuclear factor-κB (NF-κB) activation. Vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti-inflammatory properties, but the underlying mechanism remains unknown. Our aim was to investigate TRAF3 involvement on renal disease and its potential modulation by VDRAs. Method Studies were done in isolated peripheral blood mononuclear cells (PBMCs) from end-stage renal disease (ESRD) on haemodialysis (treated or not with VDRAs) patients, healthy donors or cultured renal cells. Preclinical models of renal damage were: unilateral ureteral obstruction (UUO), acute renal damage induced by Folic acid (FA) administration and TWEAK-induced renal inflammation. The effect of VDRA (paricalcitol) was tested in vitro and in vivo. Results In PBMCs isolated from ESRD, TRAF3 protein levels were downregulated compared to healthy controls, associated to activation of non-canonical NF-κB2 (downregulation of RelB or p52/NF-κB2 protein levels) and altered pro-inflammatory cytokine profile. Interestingly, treatment of those patients with the VDRA paricalcitol restored all the described features. In vitro experiments in PBMCs and tubular epithelial cells exposed to inflammatory stimuli showed that paricalcitol prevented TRAF3 downregulation, NF-κB2 activation and proinflammatory genes upregulation. Moreover, immunoprecipitation studies showed that paricalcitol diminished TRAF3 ubiquitination in the K48-linked chains and CIAP1-TRAF3 interaction. TRAF3 overexpression by CRIPS/cas9 technology mimics VDRAs effects. In preclinical models of renal damage paricalcitol inhibited renal NF-κB2 activation, reducing p52 and RelB nuclear accumulation and transcriptional activity associated to lower renal inflammation. In TWEAK-induced renal injury in VDR knockout mice, paricalcitol prevented TRAF3 downregulation and NF-κB2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol. Conclusion The present studies identify TRAF3 downregulation as a key feature promoting inflammation in CKD identifying non-canonical NF-κB activation as a key driver of inflammation in this context. The fact that the VDR is not required for paricalcitol actions suggests novel-signaling pathways involved in the anti-inflammatory effect of paricalcitol. This may allow the design of drugs that restore TRAF3 levels but are devoid of VDR-dependent effects on mineral bone metabolism, which may limit the use of VDRAs as anti-inflammatory agents.

scholarly journals In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rosangela Montanaro ◽  
Alessio D’Addona ◽  
Andrea Izzo ◽  
Carlo Ruosi ◽  
Vincenzo Brancaleone
Keyword(s):  
Inflammatory Markers ◽  
In Vitro Study ◽  
Inos Expression ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

The Vitamin D Receptor Represses Transcription of the Pituitary Transcription Factor Pit-1 Gene without Involvement of the Retinoid X Receptor

2006 ◽  
Vol 20 (4) ◽  
pp. 735-748 ◽  
Author(s):  
Samuel Seoane ◽  
Roman Perez-Fernandez
Keyword(s):  
Vitamin D ◽  
Transcription Factor ◽  
Vitamin D Receptor ◽  
Retinoid X Receptor ◽  
Breast Adenocarcinoma ◽  
Mobility Shift ◽  
Histone Deacetylase 1 ◽  
Protein Levels ◽  
Repressive Effect ◽  
Mcf 7

Abstract Pituitary transcription factor-1 (Pit-1) plays a key role in cell differentiation during organogenesis of the anterior pituitary, and as a transcriptional activator for the pituitary GH and prolactin genes. However, Pit-1 is also expressed in nonpituitary cell types and tissues. In breast tumors, Pit-1 mRNA and protein levels are increased with respect to normal breast, and in MCF-7 human breast adenocarcinoma cells, Pit-1 increases GH secretion and cell proliferation. We report here that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] administration to MCF-7 cells induces a significant decrease in Pit-1 mRNA and protein levels. By deletion analyses, we mapped a region (located between −147 and −171 bp from the transcription start site of the Pit-1 gene) that is sufficient for the repressive response to 1,25-(OH)2D3. Gel mobility shift and chromatin immunoprecipitation assays confirmed the direct interaction between the vitamin D receptor (VDR) as homodimer (without the retinoid X receptor), and the Pit-1 promoter, supporting the view that Pit-1 is a direct transcriptional target of VDR. Our data also indicate that recruitment of histone deacetylase 1 is involved in this repressive effect. This ligand-dependent Pit-1 gene inhibition by VDR in the absence of the retinoid X receptor seems to indicate a new mechanism of transcriptional repression by 1,25-(OH)2D3.

scholarly journals Niemann-Pick Type A Disease: Behavior of Neutral Sphingomyelinase and Vitamin D Receptor

2019 ◽  
Vol 20 (9) ◽  
pp. 2365 ◽  
Author(s):  
Carmela Conte ◽  
Cataldo Arcuri ◽  
Samuela Cataldi ◽  
Carmen Mecca ◽  
Michela Codini ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Synapse Formation ◽  
Type A ◽  
Acid Sphingomyelinase ◽  
Vdr Gene ◽  
Neutral Sphingomyelinase ◽  
Protein Levels ◽  
Gene And Protein Expression ◽  
Niemann Pick

Sphingomyelinase (SMase) is responsible for the breakdown of sphingomyelin (SM) with production of ceramide. The absence of acid sphingomyelinase (aSMase) causes abnormal synapse formation in Niemann-Pick type A (NPA) disease. Because high levels of ceramide in the NPA brain were demonstrated, the involvement of other SMases were supposed. In the present study we focused the attention on the neurogenic niches in the hippocampal gyrus dentatus (GD), a brain structure essential for forming cohesive memory. We demonstrated for the first time the increase of (Sex determining region Y)-box 2 (SOX2), and the down-regulation of glial fibrillary acidic protein (GFAP) NPA mice GD. Moreover, we found that the expression of Toll like receptors (TLRs), was increased in NPA mice, particularly TLR2, TLR7, TLR8 and TLR9 members. Although no significant change in neutral sphingomyelinase (nSMase) gene expression was detected in the NPA mice hippocampus of, protein levels were enhanced, probably because of the slower protein degradation rate in this area. Many studies demonstrated that vitamin D receptor (VDR) is expressed in the hippocampus GD. Unexpectedly, we showed that NPA mice exhibited VDR gene and protein expression up-regulation. In summary, our study suggests a relation between hippocampal cell differentiation defect, nSMase and VDR increase in NPA mice.

scholarly journals The Vitamin D Receptor Regulates Tissue Resident Macrophage Response to Injury

Endocrinology ◽  
2016 ◽  
Vol 157 (10) ◽  
pp. 4066-4075 ◽  
Author(s):  
Lige Song ◽  
Garyfallia Papaioannou ◽  
Hengguang Zhao ◽  
Hilary F. Luderer ◽  
Christine Miller ◽  
...  
Keyword(s):  
Vitamin D ◽  
Wound Healing ◽  
Vitamin D Receptor ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Dermal Fibroblasts ◽  
Wild Type ◽  
Macrophage Response ◽  
Protein Levels ◽  
Inflammatory Phase

Ligand-dependent actions of the vitamin D receptor (VDR) play a pleiotropic role in the regulation of innate and adaptive immunity. The liganded VDR is required for recruitment of macrophages during the inflammatory phase of cutaneous wound healing. Although the number of macrophages in the granulation tissue 2 days after wounding is markedly reduced in VDR knockout (KO) compared with wild-type mice, VDR ablation does not alter macrophage polarization. Parabiosis studies demonstrate that circulatory chimerism with wild-type mice is unable to rescue the macrophage defect in the wounds of VDR KO mice and reveal that wound macrophages are of local origin, regardless of VDR status. Wound cytokine analyses demonstrated a decrease in macrophage colony-stimulating factor (M-CSF) protein levels in VDR KO mice. Consistent with this, induction of M-CSF gene expression by TGFβ and 1,25-dihydroxyvitamin D was impaired in dermal fibroblasts isolated from VDR KO mice. Because M-CSF is important for macrophage self-renewal, studies were performed to evaluate the response of tissue resident macrophages to this cytokine. A decrease in M-CSF induced proliferation and cyclin D1 expression was observed in peritoneal resident macrophages isolated from VDR KO mice, suggesting an intrinsic macrophage abnormality. Consistent with this, wound-healing assays in mice with macrophage-specific VDR ablation demonstrate that a normal wound microenvironment cannot compensate for the absence of the VDR in macrophages and thus confirm a critical role for the macrophage VDR in the inflammatory response to injury.

scholarly journals The Potential Role of Therapeutic Dose of Low Molecular Weight Heparin (LWMH) to Attenuate Hyper-Inflammatory State in Hospitalized COVID-19 Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Mohsin Sheraz Mughal ◽  
Ikwinder Preet Kaur ◽  
Ali R. Jaffery ◽  
Chang Wang ◽  
Muhammad Asif ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Disease Severity ◽  
Inflammatory Markers ◽  
Potential Role ◽  
Hospitalized Patients ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
D Dimer ◽  
Inflammatory Effect

Introduction:The underlying pathophysiology of severe COVID-19 involves cytokine storm syndrome that is associated with an elevation of immunoinflammatory cytokines [1]. This hyper-inflammatory state has been implicated with coagulopathy among severely sick patients with COVID-19. Inflammation and coagulopathy are interlinked processes [2]. Coagulopathy has been associated with high mortality in COVID-19 patients [3]. LMWH is traditionally used for its anticoagulant and antithrombotic properties, however, its anti-inflammatory effect has not been fully elucidated. A study done by Shastri et al. suggested that LMWH can inhibit the release of different cytokines (IL-4, IL-5, IL-13, and TNF-α) [4]. Recent retrospective studies on COVID-19 illustrated that the LMWH (40-60 mg, subcutaneously every day) was associated with better prognosis as measured by (28 days of survival) in severely sick patients meeting sepsis-induced coagulopathy (SIC≥4) criteria compared to nonusers [5]. The potential role of escalated/therapeutic LMWH (1mg/kg/subcutaneously every 12 hours) remains unclear. This study involves a retrospective analysis of the potential role of an escalated dose of LMWH to alter the hyper-inflammatory state in hospitalized patients with COVID-19 and compared outcomes to those patients who received a low dose (40-60 mg, subcutaneously every day) of LMWH. Methods:Adult patients with confirmed SARS-CoV-2 infection by nasopharyngeal (NP) polymerase chain reaction (PCR) who were hospitalized from March 1st to April 20, 2020, were included. They were divided into two cohorts based on the dose of LMWH; cohort 1 (40-60 mg, subcutaneously every day) and cohort 2 (1mg/kg/subcutaneously every 12 hours). Categorical variables were compared by conducting a chi-square test or Fisher's exact test while continuous ones were compared by conducting a median two-sample test. Results:The median values of PT, PTT, INR, CRPmax, LDHmax, ferritinmax, D-dimermax, are mentioned in table 1. Incidence of thrombotic events (deep venous thrombosis, ischemic stroke, pulmonary embolism) was higher in cohort 1 (n=3, 4.8%) compared to cohort 2 (n=1, 2.6%). Cohort 2 had a higher number of patients who received ICU level of care (n=24) compared to the 6 patients in cohort 1. Out of 24 patients in cohort 2, 18 patients received invasive mechanical ventilation. The median value of length of stay in the hospital (10.0 days) and all-cause mortality (31.6 %) were higher in cohort 2 as compared to cohort 1 (p<0.05). Discussion:Infections have the ability to trigger systemic inflammation [6]. The interplay between the host system and its response to foreign pathogens can lead to the activation of coagulation pathways. SARS-CoV-2 entry via ACE-2 receptors on endothelial cells is likely associated with endothelial dysfunction. This endotheliopathy plays a significant role in COVID-19 related microcirculatory changes [7]. Severe COVID-19, a hyperinflammatory state, is marked by elevated inflammatory markers including D-dimer, ferritin, IL-6, LDH, and CRP levels. Elevated D-dimer levels have been correlated with disease severity and poor outcomes in hospitalized patients with COVID-19 [8]. The incidence of VTE and pulmonary embolism among COVID-19 ICU patients was higher in a study from France [9]. The patient population who received the escalated dose of LMWH in our study either had SIC score ≥ 4 or D-dimer ≥ 2.2 (FEU). This data indicated that the median value of peak inflammatory markers in cohort 1 was lower (p<0.05) when compared to cohort 2. Patients in cohort 2 were sicker than cohort 1, as evidenced by a statistically significant longer length of hospital stay and a higher rate of ICU admission. However, the potential dose-dependent anti-inflammatory effect of LMWH was not observed. Additional studies evaluating comorbidities and disease severity in both cohorts may yield different results. Conclusion:Aside from the known anticoagulant benefit of LMWH, there was no additional anti-inflammatory role with higher doses (1mg/kg/subcutaneously every 12 hours) of LMWH. Disclosures No relevant conflicts of interest to declare.

scholarly journals 1,25-(OH)2D3/Vitamin D receptor alleviates systemic lupus erythematosus by downregulating Skp2 and upregulating p27

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Dan Liu ◽  
Yu-Xuan Fang ◽  
Xia Wu ◽  
Wei Tan ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Inflammatory Responses ◽  
Urinary Protein ◽  
Inflammatory Factors ◽  
Systemic Lupus ◽  
Protein Levels

Abstract Background Recent evidence has suggested that the 1,25(OH)2D3/Vitamin D receptor (VDR) acts to suppress the immune response associated with systemic lupus erythematosus (SLE), a serious multisystem autoimmune disease. Hence, the aim of the current study was to investigate the mechanism by which 1,25-(OH)2D3/VDR influences SLE through regulating the Skp2/p27 signaling pathway. Methods Initially, the levels of 1,25(OH)2D3, VDR, Skp2, and p27 were measured in collected renal tissues and peripheral blood. Meanwhile, the levels of inflammatory factors, biochemical indicators (BUN, Cr, anti-nRNP IgG, anti-dsDNA IgG) and urinary protein levels were assayed in in VDRinsert and VDR-knockout mice in response to 1,25(OH)2D3 supplement. In addition, the distribution of splenic immune cells was observed in these mice. Results Among the SLE patients, the levels of 1,25(OH)2D3, VDR and p27 were reduced, while the levels of Skp2 were elevated. In addition, the levels of anti-nRNP IgG and anti-dsDNA IgG were increased, suggesting induction of inflammatory responses. Notably, 1,25(OH)2D3/VDR mice had lower concentrations of BUN and Cr, urinary protein levels, precipitation intensity of the immune complex and complement, as well as the levels of anti-nRNP IgG and anti-dsDNA IgG in SLE mice. Additionally, 1,25(OH)2D3 or VDR reduced the degree of the inflammatory response while acting to regulate the distribution of splenic immune cells. Conclusion This study indicated that 1,25-(OH)2D3/VDR facilitated the recovery of SLE by downregulating Skp2 and upregulating p27 expression, suggesting the potential of 1,25-(OH)2D3/VDR as a promising target for SLE treatment.

scholarly journals CLINICAL EVALUATION OF POTENTIAL ANTI-INFLAMMATORY EFFECT OF VITAMIN D3 ADJUVANT THERAPY FOR CHRONIC ASTHMA IN IRAQI PATIENTS

2016 ◽  
Vol 9 (1) ◽  
pp. 139 ◽  
Author(s):  
Rasha Saadi Abbas ◽  
Manal Khalid Abdulridha ◽  
Mostafa Abdalfatah Shafek
Keyword(s):  
Vitamin D ◽  
Treatment Level ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Pre Treatment ◽  
Group 2 ◽  
To Receive ◽  
Necrosis Factor ◽  
Group 1 ◽  
Inflammatory Effect

<p><strong>Objective</strong>:<strong> </strong>This study was designed to evaluate the potential anti-inflammatory effect of vitamin D<sub>3</sub> supplementation in Iraqi patients with chronic asthma.<strong> </strong></p><p><strong>Methods: </strong>Forty-four candidate patients were diagnosed with asthma during their visit to hospital allocated as 20 patients assigned to receive conventional therapy for asthma and 24 patients assigned to receive conventional therapy for asthma plus<strong> </strong>2000 I. U vitamin D<sub>3</sub> tablet for three months period. Also, 30 apparently healthy subjects were included in the study as a control group. Pulmonary function test, serum 25-OH vitamin D levels, serum Interlukin-10 (IL-10) levels, serum tumor necrosis factor alpha (TNF-α) levels were measured before and after three months therapy.</p><p><strong>Results: </strong>After three months treatment, there was a highly significant improvement in both measured and percentage of predicted value of pulmonary function test (PFT) compared to the pre-treatment value for both group 1 and group 2 patients (<em>p</em>&lt;0.01). Also, a highly significant increase in total endogenous vitamin D level in group 2 when compared to group 1 patients after three months period (<em>p</em>&lt;0.01). Group 2 patients presented with a significant increase in mean IL-10 after three months of treatment when compared to pre-treatment level (<em>p</em>&lt;0.05). The mean TNF-α level was increased non-significantly in both study groups, but the higher level was found in group 1 patients than in group 2 patients when compared to pre-treatment level (<em>p</em>&gt;0.05).</p><p><strong>Conclusion: </strong>There was a significant increase in the level of anti-inflammatory biomarker interleukin-10 (IL-10), though no clear effect on tumor necrosis factor-α (TNF-α) was noticed after three months treatment with vitamin D<sub>3</sub> supplementation.</p>

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