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1.
Adv Chronic Kidney Dis ; 26(1): 8-15, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30876622

RESUMO

Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease.


Assuntos
Hospedeiro Imunocomprometido/imunologia , Infecções/imunologia , Inflamação/imunologia , Insuficiência Renal Crônica/imunologia , Imunidade Adaptativa/imunologia , Calcitriol/imunologia , Cálcio/metabolismo , Epigênese Genética , Eritropoetina/imunologia , Fatores de Crescimento de Fibroblastos/metabolismo , Microbioma Gastrointestinal/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/genética , Imunossenescência , Infecções/epidemiologia , Ferro/imunologia , Estresse Oxidativo/imunologia , Hormônio Paratireóideo/metabolismo , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal , Renina/imunologia , Sistema Renina-Angiotensina/imunologia , Vitamina D/metabolismo
2.
J Steroid Biochem Mol Biol ; 187: 134-145, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30481575

RESUMO

Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D3 (1α,25-dihydroxyvitamin D3; 1α,25(OH)2D3) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1α,25(OH)2D3 in determining the tolDC profile. Using tracer metabolomics, we show that PFKFB4 activity is essential for glucose metabolism, especially for glucose oxidation, which is elevated upon 1α,25(OH)2D3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1α,25(OH)2D3-mediated shift in metabolism, DC profile and function, as determined by expression of inhibitory surface markers and secretion of regulatory cytokines and factors. Moreover, PFKFB4 inhibition in 1α,25(OH)2D3-treated DCs blocked their hallmark capacity to induce suppressive Tregs. This work demonstrates that alterations in the bioenergetic metabolism of immune cells are central to the immunomodulatory effects induced by 1α,25(OH)2D3.


Assuntos
Calcitriol/metabolismo , Células Dendríticas/metabolismo , Glucose/metabolismo , Fosfofrutoquinase-2/metabolismo , Linfócitos T Reguladores/metabolismo , Autoimunidade , Calcitriol/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Glucose/imunologia , Humanos , Metabolômica , Fosfofrutoquinase-2/imunologia , Linfócitos T Reguladores/imunologia
3.
J Allergy Clin Immunol ; 143(6): 2108-2119.e12, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30578876

RESUMO

BACKGROUND: Previous studies have revealed significant alterations in the skin microbiota of patients with atopic dermatitis (AD) not only in diversity and composition but also in function, and the tryptophan (Trp) metabolic pathway is attenuated in the skin microbiota of patients with AD. OBJECTIVE: We sought to assess Trp metabolites on the skin surfaces of patients with AD and to explore the function of the microbial Trp metabolites in skin inflammation in patients with AD. METHODS: A gel-patch method was developed to collect metabolites on the skin surface, which were then assessed by using liquid chromatography-tandem mass spectrometry. A mouse model of calcipotriol (MC903)-induced AD-like dermatitis was used to evaluate the effects of microbial metabolites on AD, and aryl hydrocarbon receptor (AhR)-null mice and keratinocyte cultures were used to investigate the mechanism. RESULTS: Major microbial metabolites of Trp were detected on the skin surfaces of healthy subjects, and the level of indole-3-aldehyde (IAId), an indole derivative of Trp catabolism, was significantly lower in lesional and nonlesional skin of patients with AD than that of healthy subjects. IAId significantly attenuated skin inflammation in mice with MC903-induced AD-like dermatitis, and this effect was blocked by an AhR antagonist and abolished in AhR-null mice. Furthermore, IAId was found to inhibit the MC903-induced expression of thymic stromal lymphopoietin in keratinocytes in vivo and in vitro, which was mediated by binding of AhR to the thymic stromal lymphopoietin promoter. CONCLUSION: IAId, a skin microbiota-derived Trp metabolite, negatively regulated skin inflammation in patients with AD, revealing that skin microbiota play a significant functional role in the pathogenesis of AD.


Assuntos
Dermatite Atópica/tratamento farmacológico , Indóis/uso terapêutico , Queratinócitos/fisiologia , Microbiota/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/microbiologia , Animais , Calcitriol/análogos & derivados , Calcitriol/imunologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Hidrocarboneto Arílico/genética , Pele/metabolismo , Triptofano/metabolismo , Regulação para Cima
4.
J Clin Gastroenterol ; 52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017: S86-S88, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30300262

RESUMO

Vitamin D is a group of liposoluble prohormones consisting of 5 different vitamins, the most important forms being vitamin D2 and vitamin D3. The ergocalciferol (vitamin D2) is less efficacious and derives from irradiated fungi, while colecalciferol (vitamin D3), derived from cholesterol, is synthesized via ultraviolet B rays in animal organisms. Only the ultraviolet B rays (290 to 315 nm) portion of the solar ray photolyzes 7-dehydrocholesterol in the skin to previtamin D3, which is converted subsequently to vitamin D3. Moreover, the skin makes little vitamin D from the sun at latitudes above 37 degrees north or below 37 degrees south of the equator. Calcidiol [25(OH)D] is the more stable metabolite of vitamin D in serum and the best indicator of the vitamin D status. Optimal values range are >30 ng/mL. Calcitriol [1,25(OH)2D] is the active hormone form of vitamin D. The 1,25(OH)2D binds to its nuclear receptor (vitamin D receptor), expressed in many tissues, regulating the expression of genes involved in calcium metabolism, cell differentiation, apoptosis, and immunity. About immunity, calcitriol stimulates innate immune responses by enhancing the chemotactic and phagocytotic responses of macrophages as well as the production of antimicrobial peptides. 1,25(OH)2D strongly enhances production of interleukine-10 by stimulating T regulatory cells and inhibiting Th1 and Th17 cell differentiation. Furthermore, several studies suggest that lower 25(OH)D serum levels are associated with an increased risk of respiratory infection at all ages in a dose-response manner.


Assuntos
Imunidade Inata/imunologia , Vitamina D/análogos & derivados , Vitamina D/imunologia , Animais , Calcifediol/imunologia , Calcitriol/imunologia , Humanos , Estado Nutricional , Receptores de Calcitriol/metabolismo , Infecções Respiratórias/etiologia , Pele/metabolismo , Raios Ultravioleta , Vitamina D/sangue , Deficiência de Vitamina D/complicações
5.
J Invest Dermatol ; 138(7): 1555-1563, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29474945

RESUMO

IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL-17C to its IL-17RE receptor. The antibody inhibited cutaneous inflammation in an IL-23-induced psoriatic-like skin inflammation model. In lesional skin of patients with AD, IL-17C expression levels were increased and localized to keratinocytes and infiltrating immune cells. To determine the contribution of IL-17C to AD pathogenesis, MOR106 was tested in two distinct in vivo models. In the calcipotriol-induced AD model, ear skin inflammation, TSLP, and IL-33 protein production in ears was suppressed by MOR106. Consistently, in the flaky tail strain mouse model, spontaneous development of AD-like skin inflammation was reduced by MOR106. Moreover, serum IgE levels, number of mast cells in skin and T helper type 2-related cytokines IL-4 and CCL17 in serum were all reduced. Overall, our results indicate that IL-17C is a central mediator of skin inflammation beyond psoriasis and is relevant in particular in AD.


Assuntos
Anticorpos Neutralizantes/imunologia , Dermatite Atópica/imunologia , Interleucina-17/imunologia , Psoríase/imunologia , Animais , Anticorpos Neutralizantes/uso terapêutico , Biópsia , Calcitriol/administração & dosagem , Calcitriol/análogos & derivados , Calcitriol/imunologia , Células Cultivadas , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Modelos Animais de Doenças , Feminino , Humanos , Injeções Intraperitoneais , Interleucina-17/antagonistas & inibidores , Interleucina-23/administração & dosagem , Interleucina-23/imunologia , Queratinócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Psoríase/patologia , Transdução de Sinais , Pele/imunologia , Pele/patologia
6.
J Dermatolog Treat ; 29(7): 676-681, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29466894

RESUMO

OBJECTIVE: To explore whether ozonated oil recovery atopic dermatitis (AD) via immunoregulation. METHODS: Mice were repeatedly challenged with the triplex allergens of staphylococcal enterotoxin B, ovalbumin and calcipotriol ointment on the back to develop AD lesions, and were treated with ozonated oil. The lesional skins were scanned by reflectance confocal microscopy to measure the thickness of epidermis. The skin tissues were stained. Th1-type and Th2-type cytokines in serum and in tissues were detected by ELISA and real-time PCR, respectively. RESULTS: Ozonated oil significantly inhibited inflammation and healed the lesions in 7 d. Ozonated oil inhibited NGF expression as compared to the groups treated with vehicle or PBS (p < .01).The serum proteins and lesional transcripts of Th2 cytokines including IL-4 and IL-31 were lower in the ozonated oil treated group than the groups treated with vehicle or PBS (p < .05). The IL-10 level was increased with treatment of ozonated oil (p < .01). On the other hand, the expressions of Th1 cytokines including IL-2, TNF-α, and IFN-γ in the serum were not regulated by ozonated oil. CONCLUSIONS: Our results showed that ozonated oil could suppress inflammation in an AD murine via decreasing Th2-dominant cytokines response and increasing IL-10 expression. These suggest that ozonated oil may be a potential remedy for AD.


Assuntos
Dermatite Atópica/tratamento farmacológico , Ozônio/química , Óleos Vegetais/uso terapêutico , Alérgenos/imunologia , Animais , Calcitriol/análogos & derivados , Calcitriol/imunologia , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Dermatite Atópica/patologia , Enterotoxinas/imunologia , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Óleos Vegetais/química , Pele/metabolismo , Pele/patologia , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
7.
J Immunol ; 199(12): 3952-3958, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29109124

RESUMO

The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)2D3 (calcitriol), is synthesized by the essential enzyme 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1), which can be expressed by activated immune cells. The role of endogenous calcitriol synthesis for the regulation of IgE has not been proven. In this study, we investigated IgE-responses in Cyp27b1-knockout (KO) mice following sensitization to OVA or intestinal infection with Heligmosomoides polygyrus Specific Igs and plasmablasts were determined by ELISA and ELISpot, Cyp27b1 expression was measured by quantitative PCR. The data show elevated specific IgE and IgG1 concentrations in the blood of OVA-sensitized Cyp27b1-KO mice compared with wild-type littermates (+898 and +219%). Accordingly, more OVA-specific IgG1-secreting cells are present in spleen and fewer in the bone marrow of Cyp27b1-KO mice. Ag-specific mechanisms are suggested as the leucopoiesis is in general unchanged and activated murine B and T lymphocytes express Cyp27b1 Accordingly, elevated specific IgE concentrations in the blood of sensitized T cell-specific Cyp27b1-KO mice support a lymphocyte-driven mechanism. In an independent IgE-inducing model, i.e., intestinal infection with H. polygyrus, we validated the increase of total and specific IgE concentrations of Cyp27b1-KO compared with wild-type mice, but not those of IgG1 or IgA. We conclude that endogenous calcitriol has an impact on the regulation of IgE in vivo. Our data provide genetic evidence supporting previous preclinical and clinical findings and suggest that vitamin D deficiency not only promotes bone diseases but also type I sensitization.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/fisiologia , Calcitriol/imunologia , Switching de Imunoglobulina , Imunoglobulina E/sangue , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/deficiência , Animais , Linfócitos B/imunologia , Medula Óssea/imunologia , Calcitriol/biossíntese , Calcitriol/deficiência , Feminino , Helmintíase Animal/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Enteropatias Parasitárias/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nematospiroides dubius/imunologia , Especificidade de Órgãos , Ovalbumina/imunologia , Receptores de Calcitriol/fisiologia , Baço/imunologia , Linfócitos T/imunologia , Deficiência de Vitamina D/imunologia
8.
Transpl Immunol ; 43-44: 3-10, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28757397

RESUMO

BACKGROUND: Vitamin D has shown an immune-modulatory effect in different studies. Vitamin D stimulates Tregs and inhibits Th17 cells. The immune-modulatory role of vitamin D in chronic kidney disease (CKD) and renal transplant patients is unclear. We measured whether different serum levels of vitamin D were associated with an increased or decreased presence of lymphocyte subsets including Treg and Th17 cells in end-stage renal disease (ESRD) and renal transplant recipients. METHODS: Eighty-seven renal transplant recipients and 53 end-stage renal disease (ESRD) patients were enrolled in this study. The absolute counts of CD4+ and CD8+ T, CD16+ CD56+ NK, CD19+ B, CD4+ CD25+ CD127- Foxp3+ (Tregs), Helios+ Tregs, CD38+ Tregs, and CD4+ CD17+ (Th17) cells were analyzed in peripheral blood in both patient groups. In addition, serum 25 (OH) D3, 1, 25 (OH)2 D3, IL-6, IL-17, IL-23, and TGF-ß1 were measured. The association between lymphocyte subset counts and 1, 25 (OH)2 D3 or 25 (OH) D3 was studied, as was the association between serum IL-6, IL-17, IL-23, or TGF-ß1 and 1,25 (OH)2 D3 or 25 (OH) D3. RESULTS: Serum 25 (OH) D3 and 1,25 (OH)2 D3 levels were not independently associated with peripheral CD4+ T, CD19+ B, CD16+ CD56+ NK, Treg, or Th17 cell counts. In contrast to serum 25 (OH) D3, serum1, 25 (OH)2 D3 was positively associated with CD8+ T cells counts in renal transplant recipients. CONCLUSION: Our findings indicate low utility of serum 25 (OH) D3 and 1, 25 (OH)2 D3 levels in predicting a change in lymphocyte subset counts in ESRD and renal transplant patients.


Assuntos
Calcifediol/sangue , Calcitriol/sangue , Falência Renal Crônica/sangue , Transplante de Rim , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Adulto , Contagem de Linfócito CD4 , Calcifediol/imunologia , Calcitriol/imunologia , Citocinas/imunologia , Feminino , Humanos , Falência Renal Crônica/imunologia , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/imunologia , Células Th17/patologia
9.
Mol Med Rep ; 15(4): 2273-2279, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28259913

RESUMO

Epithelial-mesenchymal transition (EMT) has been recognized to accelerate peritoneal membrane dysfunction. 1,25(OH)2D3/vitamin D receptor (VDR) is important for preventing various types of EMT in vivo. However, its function on EMT and inflammation of human peritoneal mesothelial cells (HPMCs) remains to be elucidated. Therefore, the present study investigated the effects of 1,25(OH)2D3/VDR on high glucose (HG)­induced EMT and inflammation in HPMCs and the underlying molecular mechanism. It was determined that HG reduced VDR expression, increased inflammatory cytokine expression, including transforming growth factor ß (TGFß) and interleukin­6 (IL­6) and phosphorylated­SMAD family member 3 (p­Smad3) expression. EMT was promoted as the expression level of the epithelial marker E­cadherin was reduced, whereas expression levels of the mesenchymal markers α­SMA and FN were increased. 1,25(OH)2D3 pretreatment inhibited the expression of inflammatory cytokines in HPMCs and attenuated HG­induced EMT, possibly through inhibition of the TGFß/Smad pathway by binding to its receptor VDR.


Assuntos
Calcitriol/imunologia , Células Epiteliais/imunologia , Transição Epitelial-Mesenquimal , Glucose/imunologia , Receptores de Calcitriol/imunologia , Transdução de Sinais , Linhagem Celular , Citocinas/imunologia , Células Epiteliais/citologia , Humanos , Inflamação/imunologia , Peritônio/citologia , Peritônio/imunologia , Proteína Smad3/imunologia , Fator de Crescimento Transformador beta/imunologia
10.
Scand J Immunol ; 85(2): 95-103, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27896829

RESUMO

Autoimmune diseases are pathological conditions characterized by abnormal responses, accompanied by autoantibodies to self-molecules. The role of vitamin D in autoimmune diseases has increased significantly in the recent past from its functions in calcium and phosphate homoeostasis, and it is now involved in the regulations and proliferations of Th1 and Th17 lymphocyte. 1α,25(OH)2D3 is very important in ameliorations of inflammatory disorders arising from autoimmune diseases, but the mechanism by which this is performed is still a bone of contentions. This review aimed to highlight the existing facts about the roles of Vitamin D in the treatment and management of autoimmune diseases. An extensive online literature search was conducted using PubMed, MEDLINE and Scopus. Accumulated bodies of research evidence are available which demonstrates that Vitamin D has a very important part to play in the regulation of immune responses in autoimmune diseases. Some of the authors suggested that Vitamin D3 carry-out its immunosuppressive and immune modulatory action, through its actions on antigen-presenting cells and activated T and B cells with the help of Vitamin D receptors present on the each of these cells. Vitamin D supplementation assists in autoimmune disorders by making qualitative and quantitative changes in the immune system (downregulation of Th1 and upregulations of Th2 cells). This resulted in the body to be more tolerant of self and less likely to mount autoimmune responses.


Assuntos
Doenças Autoimunes/imunologia , Calcitriol/imunologia , Fatores Imunológicos/imunologia , Imunossupressores/imunologia , Vitaminas/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Calcitriol/uso terapêutico , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Modelos Imunológicos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Vitaminas/uso terapêutico
11.
Nutrients ; 8(12)2016 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-27973447

RESUMO

Vitamin D induces a diverse range of biological effects, including important functions in bone health, calcium homeostasis and, more recently, on immune function. The role of vitamin D during infection is of particular interest given data from epidemiological studies suggesting that vitamin D deficiency is associated with an increased risk of infection. Vitamin D has diverse immunomodulatory functions, although its role during bacterial infection remains unclear. In this study, we examined the effects of 1,25(OH)2D3, the active metabolite of vitamin D, on peripheral blood mononuclear cells (PBMCs) and purified immune cell subsets isolated from healthy adults following stimulation with the bacterial ligands heat-killed pneumococcal serotype 19F (HK19F) and lipopolysaccharide (LPS). We found that 1,25(OH)2D3 significantly reduced pro-inflammatory cytokines TNF-α, IFN-γ, and IL-1ß as well as the chemokine IL-8 for both ligands (three- to 53-fold), while anti-inflammatory IL-10 was increased (two-fold, p = 0.016) in HK19F-stimulated monocytes. Levels of HK19F-specific IFN-γ were significantly higher (11.7-fold, p = 0.038) in vitamin D-insufficient adults (<50 nmol/L) compared to sufficient adults (>50 nmol/L). Vitamin D also shifted the pro-inflammatory/anti-inflammatory balance towards an anti-inflammatory phenotype and increased the CD14 expression on monocytes (p = 0.008) in response to LPS but not HK19F stimulation. These results suggest that 1,25(OH)2D3 may be an important regulator of the inflammatory response and supports further in vivo and clinical studies to confirm the potential benefits of vitamin D in this context.


Assuntos
Proteínas de Bactérias/imunologia , Calcitriol/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Streptococcus pneumoniae , Deficiência de Vitamina D/imunologia , Vitaminas/farmacologia , Adulto , Calcitriol/imunologia , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Leucócitos Mononucleares/imunologia , Ligantes , Lipopolissacarídeos , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo , Deficiência de Vitamina D/sangue , Adulto Jovem
12.
Nat Commun ; 7: 10213, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26750596

RESUMO

Effector CD8(+) T cells convert from IFN-γ(+) (Tc1) to IL-13(+) (Tc2) cells in the presence of IL-4. Underlying regulatory mechanisms are not fully defined. Here, we show that addition of 1,25D3, the active form of vitamin D3, during CD8(+) T-cell differentiation prevents IL-4-induced conversion to IL-13-producers. Transfer of 1,25D3-treated CD8(+) T cells into sensitized and challenged CD8(+)-deficient recipients fails to restore development of lung allergic responses. 1,25D3 alters vitamin D receptor (VDR) recruitment to the Cyp11a1 promoter in vitro and in vivo in the presence of IL-4. As a result, protein levels and enzymatic activity of CYP11A1, a steroidogenic enzyme regulating CD8(+) T-cell conversion, are decreased. An epistatic effect between CYP11A1 and VDR polymorphisms may contribute to the predisposition to childhood asthma. These data identify a role for 1,25D3 in the molecular programming of CD8(+) T-cell conversion to an IL-13-secreting phenotype through regulation of steroidogenesis, potentially governing asthma susceptibility.


Assuntos
Asma/imunologia , Calcitriol/imunologia , Enzima de Clivagem da Cadeia Lateral do Colesterol/imunologia , Receptores de Calcitriol/imunologia , Linfócitos T Citotóxicos/imunologia , Adolescente , Transferência Adotiva , Alérgenos , Animais , Asma/genética , Asma/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Calcitriol/metabolismo , Estudos de Casos e Controles , Criança , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Imunoprecipitação da Cromatina , Simulação por Computador , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Predisposição Genética para Doença , Humanos , Immunoblotting , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-13/imunologia , Interleucina-13/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Ovalbumina , Polimorfismo de Nucleotídeo Único , Pregnenolona/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Scand J Immunol ; 83(2): 83-91, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26678915

RESUMO

In the past, vitamin D was known for its classical, skeletal action as a regulator of calcium and bone homoeostasis. Currently, vitamin D was found to have a role in numerous physiological processes in the human body; thus, vitamin D has pleiotropic activity. The studies carried out in the past two decades showed the role of vitamin D in the regulation of immune system functions. Basically, these effects may be mediated not only via endocrine mechanism of circulating calcitriol but also via paracrine one (based on cell-cell communication that leads to production of signal inducing the changes in nearby/adjacent cells and modulating their differentiation or behaviour) and intracrine mechanism (the action of vitamin D inside a cell) of 1,25-dihydroxycholecalciferol (1,25(OH)2 D3 ) synthetized from its precursor 25-hydroxyvitamin D3 (25(OH)D3 ). Both vitamin D receptor (VDR) and 25-hydroxyvitamin D3 1-α-hydroxylase (CYP27B1) are expressed in several types of immune cells (i.e. antigen presenting cells, T and B cells), and thus, they are able to synthetize the bioactive form of vitamin D that modulates both the innate and adaptive immune system. This review discusses the role of vitamin D as regulator of immune system, and our understanding of how vitamin D regulates both adaptive and innate immunity as well as inflammatory cascade on the cellular level.


Assuntos
Colecalciferol/imunologia , Colecalciferol/metabolismo , Fatores Imunológicos/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Imunidade Adaptativa , Animais , Apresentação do Antígeno , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Calcifediol/imunologia , Calcifediol/metabolismo , Calcitriol/imunologia , Calcitriol/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Imunidade Inata , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
J Steroid Biochem Mol Biol ; 164: 239-245, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26343449

RESUMO

The nuclear vitamin D receptor (VDR) is generally recognized as a ligand-dependent transcription factor that mediates the actions of its natural ligand, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) on multiple target genes involved in mineral homeostasis, bone development, as well as immune reactivity. As the VDR is widely distributed in nearly all cells of the body, it implies that the vitamin D endocrine system may regulate many cell types and functions. Experiments in VDR null mice established that the VDR has intrinsically critical roles in skin and keratinocyte biology but not in immune responses. Oppositely, absence of the VDR ligand is linked to susceptibility to autoimmunity, illustrating a potential role for the unliganded VDR in the immune system. This discrepancy stimulated us to further investigate the impact of the VDR on the phenotype and function of myeloid dendritic cells (DCs) generated ex vivo from bone marrow precursors of VDR null (with a truncated VDR) and VDR ΔAF2 mice (with a mutated C-terminal activation factor 2 domain thus rendering ligand-induced gene transcription impossible). Absent or unliganded VDR did not affect bone marrow-derived myeloid DC generation. DCs obtained from VDR null and VDR ΔAF2 bone marrow cells had comparable MHC-II, and costimulatory molecule CD86, CD80 and CD40 expression than DCs from wild-type bone marrow cells. Additionally, an unliganded VDR did not affect the cytokine production nor the antigen-specific T cell stimulatory capacity of bone marrow-derived DCs. In conclusion, we showed that although clear effects of 1α,25-dihydroxyvitamin D3 are described on DC generation, absence of VDR or presence of an unliganded VDR does not affect the profile and function of ex vivo generated bone marrow-derived DCs.


Assuntos
Células da Medula Óssea/imunologia , Calcitriol/metabolismo , Células Dendríticas/imunologia , Receptores de Calcitriol/genética , Linfócitos T/imunologia , Animais , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígeno B7-2/genética , Antígeno B7-2/imunologia , Células da Medula Óssea/citologia , Antígenos CD40/genética , Antígenos CD40/imunologia , Calcitriol/imunologia , Diferenciação Celular , Células Dendríticas/citologia , Regulação da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Ligantes , Camundongos , Camundongos Knockout , Ligação Proteica , Receptores de Calcitriol/deficiência , Linfócitos T/citologia
15.
Nutrients ; 7(9): 8127-51, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26402698

RESUMO

Studies over the last two decades have revealed profound immunomodulatory aspects of vitamin D on various aspects of the immune system. This review will provide an overview of Vitamin D metabolism, a description of dendritic cell subsets, and highlight recent advances on the effects of vitamin D on dendritic cell function, maturation, cytokine production and antigen presentation. The active form of vitamin D, 1,25(OH)2D3, has important immunoregulatory and anti-inflammatory effects. Specifically, the 1,25(OH)2D3-Vitamin D3 complex can affect the maturation and migration of many dendritic cell subsets, conferring a special immunoregulatory role as well as tolerogenic properties affecting cytokine and chemokine production. Furthermore, there have been many recent studies demonstrating the effects of Vitamin D on allergic disease and autoimmunity. A clear understanding of the effects of the various forms of Vitamin D will provide new opportunities to improve human health.


Assuntos
Calcitriol/metabolismo , Células Dendríticas/metabolismo , Imunidade Adaptativa , Animais , Calcitriol/imunologia , Calcitriol/uso terapêutico , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Suplementos Nutricionais , Humanos , Imunidade Inata , Mediadores da Inflamação/metabolismo , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Transdução de Sinais
16.
Isr Med Assoc J ; 17(2): 80-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26223082

RESUMO

BACKGROUND: Vitamin D is a pivotal factor in calcium homeostasis and exerts immunomodulatory effects. Hypovitamin D has been demonstrated in systemic sclerosis (SSc) patients and may be related to more severe disease of longer duration and with extensive skin involvement. OBJECTIVES: To seek anti-vitamin D antibodies in SSc patients, as found by previous research in patients with systemic lupus erythematosus (SLE). METHODS: The study included 54 SSc patients and 41 volunteers. Immunoglobulin (Ig) G and IgM autoantibody levels against 25(OH)D and 1,25(OH)D were obtained from patients and controls and were compared. SSc patients were assessed for autoantibody profile and disease severity. RESULTS: Vitamin D antibodies were present in 87% of SSc patients and 42% of controls. Higher levels of anti-25(OH)D IgM antibodies were detected in SSc patients compared to controls (0.48 ± 0.22 vs. 0.29 ± 0.29, respectively, P = 0.002); however, IgG levels were lower in the SSc patients. No such discriminative. effect was found regarding anti-1,25(OH)D antibodies between SSc and controls. No correlation was found between,vitamin D antibodies and other autoantibodies, disease severity, or target organ damage. CONCLUSIONS: To the best of our knowledge; this is the first study of these novel, anti-vitamin D antibodies in SSc patients and the first time a correlation between IgM 25(OH) vitamin D antibodies and scleroderma has been identified. Further research on the pathophysiological significance and therapeutic potential of vitamin D is required.


Assuntos
25-Hidroxivitamina D 2/imunologia , Autoanticorpos/sangue , Calcitriol/imunologia , Escleroderma Sistêmico , Deficiência de Vitamina D , Adulto , Idoso , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/fisiopatologia , Índice de Gravidade de Doença , Estatística como Assunto , Deficiência de Vitamina D/etiologia , Deficiência de Vitamina D/imunologia
17.
Int Immunol ; 27(5): 237-44, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25574039

RESUMO

Active vitamin D [1,25-dihydroxyvitamin D3 (1,25D3)] blocks the development of experimental autoimmune diseases. However, the molecular and immunobiological mechanisms underlying 1,25D3's anti-inflammatory properties are not fully understood. We employed a murine model of experimental autoimmune encephalomyelitis (EAE) in order to determine the role of NKT cells in 1,25D3-mediated protection from EAE. Wild-type (WT) mice or mice lacking all NKT cells (CD1d(-/-)) or invariant NKT cells (Jα18(-/-)) were fed control or 1,25D3-supplemented diets. All mice fed with the control diet developed severe EAE. 1,25D3 treatment of WT mice protected them from developing EAE. CD1d(-/-) and Jα18(-/-) mice treated with 1,25D3 were not protected to the same extent as WT mice. Myelin oligodendrocyte glycoprotein-specific IL-17 and IFN-γ production was significantly reduced in 1,25D3 WT mice compared with WT but was not decreased in 1,25D3 CD1d(-/-) mice compared with CD1d(-/-) mice. IL-4(-/-) mice were utilized to determine how IL-4 deficiency affects susceptibility to EAE. IL-4(-/-) mice were not protected from developing EAE by α-galactosylceramide (α-GalCer) or 1,25D3 treatment. Furthermore, 1,25D3 treatment of splenocytes in vitro decreased α-GalCer-induced IL-17 and increased IL-4, IL-5 and IL-10 production. 1,25D3 alters the cytokine profile of invariant NKT cells in vitro. These studies demonstrate that NKT cells are important mediators of 1,25D3-induced protection from EAE in mice and NKT cell-derived IL-4 may be an important factor in providing this protection.


Assuntos
Calcitriol/imunologia , Encefalomielite Autoimune Experimental/imunologia , Interleucina-4/metabolismo , Esclerose Múltipla/imunologia , Células T Matadoras Naturais/fisiologia , Animais , Antígenos CD1d/genética , Autoantígenos/imunologia , Calcitriol/farmacologia , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/imunologia , Células T Matadoras Naturais/efeitos dos fármacos
18.
PLoS One ; 9(5): e96695, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24792400

RESUMO

The active form of vitamin D3, 1,25(OH)2D3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4+ effector T cells. The biological actions of 1,25(OH)2D3 are mediated by the vitamin D receptor (VDR) and are believed to correlate with the VDR protein expression level in a given cell. The aim of this study was to determine if and how 1,25(OH)2D3 by itself regulates VDR expression in human CD4+ T cells. We found that activated CD4+ T cells have the capacity to convert the inactive 25(OH)D3 to the active 1,25(OH)2D3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)2D3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4+ T cells. Furthermore, 1,25(OH)2D3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)2D3 stabilizes the VDR by protecting it from proteasomal degradation. Finally, we demonstrate that proteasome inhibition leads to up-regulation of VDR protein expression and increases 1,25(OH)2D3-induced gene activation. In conclusion, our study shows that activated CD4+ T cells can produce 1,25(OH)2D3, and that 1,25(OH)2D3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4+ T cells by protecting the VDR against proteasomal degradation.


Assuntos
Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Calcitriol/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores de Calcitriol/metabolismo , Antifúngicos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Inibidores do Citocromo P-450 CYP3A/farmacologia , Ácidos Graxos Insaturados/farmacologia , Humanos , Cetoconazol/farmacologia , Ativação Linfocitária , Complexo de Endopeptidases do Proteassoma/imunologia , Inibidores de Proteassoma/farmacologia , Transporte Proteico/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Receptores de Calcitriol/genética , Receptores de Calcitriol/imunologia , Regulação para Cima/efeitos dos fármacos
19.
Eur J Immunol ; 44(6): 1781-90, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24643654

RESUMO

The active vitamin D metabolite 1α,25-dihydroxyvitamin D (1,25[OH]2 D) potently inhibits DC priming of T-cell activation, suggesting that it mediates a homeostatic role in this context. Therefore, careful regulation of 1,25[OH]2 D levels is necessary to avoid inappropriate inhibition of T-cell activation. Cell-autonomous control of vitamin D activity can be modulated by the action of the vitamin D-activating and -inactivating hydroxylases, CYP27B1, and CYP24A1, respectively. We show that in comparison to macrophages, human monocyte-derived DCs exhibit significantly less activation of 25-dihydroxyvitamin D to 1,25[OH]2 D, and that DCs predominantly express a truncated CYP27B1 transcript that may contribute to the deficiency in activation of vitamin D. Furthermore, in response to stimulation with 1,25[OH]2 D, upregulation of the inactivating enzyme CYP24A1 curtailed the functional effects of vitamin D in DCs, but not macrophages. Production of 1,25[OH]2 D by macrophages was adequate to induce expression of vitamin D-responsive genes by DCs, inhibit DC maturation in response to innate immune stimulation and DC-dependent T-cell responses. Our data suggest that in comparison to macrophages, differential regulation of hydroxylases limits autocrine vitamin D activity in DCs, and that paracrine activation of vitamin D exerts a more potent mechanism for homeostatic control of DC function.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/imunologia , Calcitriol/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/fisiologia , Esteroide Hidroxilases/imunologia , Linfócitos T/imunologia , Células Dendríticas/citologia , Feminino , Homeostase/fisiologia , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Monócitos/citologia , Monócitos/imunologia , Linfócitos T/citologia , Vitamina D3 24-Hidroxilase
20.
J Gastroenterol Hepatol ; 28 Suppl 1: 49-55, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23855296

RESUMO

Traditionally regarded as a typical vitamin regulating calcium and phosphorus homeostasis, vitamin D is now discovered as a highly versatile molecule with emerging roles in immunity, cancer, infectious diseases, fibrosis, fatty liver diseases, and alcoholic liver diseases. A large body of clinical evidence has demonstrated the prevalence and risks of vitamin D deficiency in various chronic diseases. Biologically active vitamin D, 1,25-dihydroxylvitamin D3, is synthesized in two distinct systems. In addition to the classic two-step hydroxylation in the liver and kidneys, 1,25-dihydroxylvitamin D3 can also be produced locally by immune cells in response to infection. The bioactive vitamin D generated in these two pools apparently functions differently: while the former facilitates calcium adsorption and homeostasis, the latter confers immune regulation. The immune regulatory functions of vitamin D are demonstrated by induction of antimicrobial peptides, suppression of innate immune response, induction of Th2 cytokines, and stimulation of T-regulatory T cells. Vitamin D deficiency or insufficiency is overwhelmingly associated with viral hepatitis, cirrhosis, and fatty liver diseases. Recent clinical trials have shown that vitamin D supplements significantly enhance the efficacy of interferon plus ribavirin therapy through sustained virological response. A recent study showed that 25-dihydroxyvitamin D rather than 1,25-dihydroxyvitamin D could directly suppress hepatitis C virus assembly. Moreover, clinical evidence has shown that vitamin D deficiency is associated with alcoholic and non-alcoholic fatty liver diseases. In this review, we highlight some recent advances in vitamin D researches and clinical trails.


Assuntos
Sistema Imunitário/imunologia , Hepatopatias/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/fisiologia , Animais , Calcitriol/biossíntese , Calcitriol/imunologia , Calcitriol/fisiologia , Cálcio/metabolismo , Ensaios Clínicos como Assunto , Hepacivirus/fisiologia , Homeostase/imunologia , Humanos , Hidroxilação , Sistema Imunitário/metabolismo , Inflamação/imunologia , Fígado/metabolismo , Hepatopatias/imunologia , Montagem de Vírus/efeitos dos fármacos , Vitamina D/análogos & derivados , Vitamina D/imunologia , Vitamina D/farmacologia , Vitamina D/uso terapêutico
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