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1.
J Agric Food Chem ; 67(34): 9522-9531, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31379161

RESUMO

The imbalance of T lymphocyte subsets substantially conduces to disturbed intestinal immune system and succeeding colonic tissue damage in inflammatory bowel diseases. It is considered that regulation of phytochemicals on cytokine production potentially provides a broad prospect for the exploitation of immunomodulatory agents. Here, we reported that oral administration of feruloylated oligosaccharides (FOs) effectively alleviated mice colitis disease induced by dextran sulfate sodium (DSS). FOs decreased the percentage of T helper (Th)17 cells and downregulated the production of Th17-specific cytokines. In contrast, FOs increased the percentage of regulatory T (Treg) cells and elevated the production of Treg-specific cytokines in colons of DSS-challenged mice. These results indicated that FOs restored the immunologic equilibrium of Th17 and Treg subsets, hereby ameliorating the deterioration of colitis. Furthermore, FOs diminished the secretion of interleukin (IL)-23 and IL-6 but enhanced the transforming growth factor-ß1 (TGF-ß1) in dendritic cells in vitro and in vivo, which contributed to the restoration of Th17 and Treg cells immune balance. The mechanistic analysis showed that the regulation of FOs on IL-23 and IL-6 was associated with the nuclear factor-κ-gene binding signaling pathway and TGF-ß1 with mitogen-activated protein kinase-activator protein 1 signaling pathway. Taken together, oral administration of FOs exerted potent immunomodulatory effects against mice colitis via restoring the immune balance of Th17 and Treg cells.


Assuntos
Colite/tratamento farmacológico , Oligossacarídeos/administração & dosagem , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Humanos , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligossacarídeos/química , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
2.
Immunity ; 51(2): 367-380.e4, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31350179

RESUMO

Epithelial barrier defects are implicated in the pathogenesis of inflammatory bowel disease (IBD); however, the role of microbiome dysbiosis and the cytokine networks orchestrating chronic intestinal inflammation in response to barrier impairment remain poorly understood. Here, we showed that altered Schaedler flora (ASF), a benign minimal microbiota, was sufficient to trigger colitis in a mouse model of intestinal barrier impairment. Colitis development required myeloid-cell-specific adaptor protein MyD88 signaling and was orchestrated by the cytokines IL-12, IL-23, and IFN-γ. Colon inflammation was driven by IL-12 during the early stages of the disease, but as the mice aged, the pathology shifted toward an IL-23-dependent inflammatory response driving disease chronicity. These findings reveal that IL-12 and IL-23 act in a temporally distinct, biphasic manner to induce microbiota-driven chronic intestinal inflammation. Similar mechanisms might contribute to the pathogenesis of IBD particularly in patients with underlying intestinal barrier defects.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Mucosa Intestinal/patologia , Microbiota/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Humanos , Inflamação , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-23/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Quimeras de Transplante
3.
Fish Shellfish Immunol ; 92: 315-321, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202965

RESUMO

Mammalian Interleukin (IL)-23 is a heterodimeric cytokine with an IL-23-specific P19 subunit and a P40 subunit shared with IL-12, and plays a key role in the regulation of cell differentiation as well as inflammation. We previously demonstrated the existence of three soluble fish Interleukin (Il)-23 isoforms consist of a single P19 and one of three P40 isoforms (P40a/b/c) in grass carp. In the present study, three recombinant grass carp Il-23 (rgcIl-23) isoforms were prepared by linking gcP19 and gcP40a/b/c in a prokaryotic expression system, and then their functional properties were verified in grass carp head kidney leukocytes (HKLs). All three rgcIl-23 isoforms showed the bioactivities to divergently upregulate the mRNA expression of Th17 signature cytokines (il17a/f1, il21, il22 and il26) as well as Il-23 receptor (il23r) in HKLs. Moreover, they also promoted gcIl-17a/f1 secretion in a dose-dependent manner, strengthening their roles in Th17-like response. Furthermore, induction of il17a/f1 and il23r transcription by rgcIl-23 was blocked by a STAT3 inhibitor in grass carp HKLs, suggesting the involvement of STAT3 signaling in these inductions. Taken together, we for the first time identified the bioactivities of fish Il-23 isoforms and particularly revealed the existence of Il-23/Il-17a/f1 axis in fish, thereby advancing our understanding of Th17-like responses in fish immunity.


Assuntos
Carpas/genética , Carpas/imunologia , Proteínas de Peixes/genética , Interleucina-23/genética , Células Th17/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica , Rim Cefálico/imunologia , Interleucina-23/metabolismo , Leucócitos/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Transdução de Sinais/imunologia
4.
Biomed Pharmacother ; 115: 108877, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054511

RESUMO

Accumulating evidence suggests that long-noncoding RNA (lncRNA) plays important roles in hepatitis B virus (HBV) infections. However, the mechanism underlying how lncRNA regulate hepatocellular carcinoma process remains largely unknown. In this study we found that the expression of LINC01152 was significantly increased in HBV positive HCC tissues and cells and was induced by HBx in vitro. The overexpression of LINC01152 could increases HCC cell proliferation and promotes tumor formation in nude mice. Mechanistically, HBx could increase the transcription of LINC01152. Elevated LINC01152 binds to the promoter region of IL-23, promoting its transcriptional activity and upregulating the levels of Stat3 and p-Stat3. Our findings suggest that LINC01152 plays an important role in HBV-related hepatocellular carcinoma development and may serve as a therapeutic marker for hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/metabolismo , Interleucina-23/metabolismo , Neoplasias Hepáticas/metabolismo , RNA Longo não Codificante/metabolismo , Transativadores/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-23/genética , Conformação de Ácido Nucleico , RNA Longo não Codificante/genética , RNA Viral , Transativadores/genética
5.
J Dermatol ; 46(6): 482-497, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062408

RESUMO

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of psoriasis and is elevated in lesional psoriatic skin. Different murine models have been developed to mimic this pathophysiology each carrying specific merits and limitations. In an attempt to address some of these limitations, B10.RIII mice received a single hydrodynamic injection of IL-23 minicircles (MC) to induce hepatic transcription and the endogenous production of IL-23. Plasma and ear IL-23 levels were dose-dependently (0.3-3 µg) increased in MC injected mice and were sustained over the 14-day study duration. Beginning on day 7 post-injection, mice developed dose-related ear inflammation, histologically confirmed increases in epidermal and dermal area, as well as enhanced neutrophil and macrophage content. Flow cytometry demonstrated increased levels of granulocytes, T cells and monocytes/macrophages in the ear skin, with T cells identified as the main cellular source of IL-17A. Evaluation of mRNA and protein showed time-dependent, increased levels of the IL-23/IL-17 pathway and inflammatory/microbial cytokines/chemokines in the ear which differed kinetically from circulating levels. An anti-IL-23p40 antibody was assessed following both prophylactic administration and administration once the disease was established. Prophylactic dosing completely prevented the development of the ear phenotype across endpoints. Treatment administration showed a dose-related response, with a maximum inhibition of 64-94%, depending on endpoint. These data demonstrate that the IL-23 MC model is a useful approach to study IL-23/IL-17-driven skin inflammation and may facilitate preclinical assessment of novel therapies.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Interleucina-17/imunologia , Interleucina-23/imunologia , Psoríase/imunologia , Animais , DNA Circular/administração & dosagem , DNA Circular/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnicas de Transferência de Genes , Humanos , Interleucina-17/metabolismo , Interleucina-23/antagonistas & inibidores , Interleucina-23/genética , Masculino , Camundongos , Psoríase/sangue , Psoríase/tratamento farmacológico , Psoríase/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Pele/imunologia , Pele/patologia , Resultado do Tratamento
6.
Genes Immun ; 20(5): 415-425, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31000797

RESUMO

Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function, and diminished quality of life, as well as for society, because of the associated high health-care costs and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies. The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies. Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.


Assuntos
Predisposição Genética para Doença , Doenças do Sistema Imunitário/genética , Interleucina-17/imunologia , Interleucina-23/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Interleucina-17/genética , Interleucina-23/genética
7.
EBioMedicine ; 41: 333-344, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827928

RESUMO

BACKGROUND: Innate lymphoid cells (ILCs) are a newly discovered family of immune cells that have similar cytokine-secreting profiles as T helper cell subsets. Although ILCs are critical for host defense against infections and tissue homeostasis, their roles in tumor development are not well established. METHODS: We studied the function of ILC3 cells in the liver for the development of hepatocellular carcinoma (HCC) in murine HCC models using flow cytometry, adoptive transfer, and in vitro functional assays. FINDINGS: We found that ILC3 lacking the natural cytotoxicity-triggering receptor (NCR-ILC3) promoted the development of HCC in response to interleukin 23 (IL-23). IL-23 serum level is elevated in HCC patients and its high expression is associated with poor clinical outcomes. We found that IL-23 could promote tumor development in murine HCC tumor models. IL-23 promoted the expansion of NCR-ILC3 and its differentiation from group 1 ILCs (ILC1s). Furthermore, NCR-ILC3 initiated IL-17 production upon IL-23 stimulation and directly inhibited CD8+ T cell immunity by promoting lymphocyte apoptosis and limiting their proliferation. INTERPRETATION: Together, our findings suggest that NCR-ILC3 initiates the IL-17-rich immunosuppressive tumor microenvironment and promotes the development of HCC, thus may serve as a promising target for future cancer immunotherapy. FUND: This work was supported by grants from National Natural Science Foundation of China (81471586, 81571556), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the collaborative Innovation Center of Hematology, start-up grant from National University of Singapore, the Cancer Prevention and Research Institute of Texas CPRIT (RR180017), and the National Cancer Institute's Cancer Center Support (Core) Grant CA016672 (to The University of Texas MD Anderson Cancer Center).


Assuntos
Carcinoma Hepatocelular/patologia , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Neoplasias Hepáticas/patologia , Animais , Apoptose , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Imunidade Inata , Interleucina-12/metabolismo , Interleucina-17/análise , Interleucina-23/análise , Interleucina-23/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidades Proteicas/deficiência , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Transplante Homólogo
8.
Int J Rheum Dis ; 22(4): 715-724, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30740926

RESUMO

AIM: To evaluate the association of ERAP1 gene single nucleotide polymorphisms (SNPs) with the risk of ankylosing spondylitis (AS) and their role in modulation of the inflammatory interleukin (IL)-17/IL-23 axis in the disease. METHODS: For genotyping, 190 AS cases and 190 healthy controls were enrolled. After DNA extraction, all the subjects were genotyped for rs17482078, rs469876, and rs27038 polymorphisms using single specific primer polymerase chain reaction (PCR) assay. After isolation of peripheral blood mononuclear cells, RNA extraction and complementary DNA synthesis, real-time PCR using SYBR Green master mix was employed to determine messenger RNA (mRNA) expression of IL-17A and IL-23 in PBMCs. Using enzyme-linked immunosorbent assay, the concentration of these cytokines was determined in serum samples. RESULTS: It was observed that the A allele of rs27038 polymorphism significantly increased AS risk (odds ratio [OR] = 1.53, 95% CI =1.11-2.12; P = 0.0096). Moreover, AA and AG genotypes of this SNP were associated with increased (OR = 2.89, 95% CI = 1.42-5.85; P = 0.0031) and decreased (OR = 0.57, 95% CI = 0.36-0.92; P = 0.021), respectively, risk of the disease. The rs27038 SNP was associated with C-reactive protein level. There were significantly increased mRNA and serum concentrations of both IL-17A and IL-23 in AS patients compared with controls. Furthermore, AS patients with the AA in comparison to other genotypes for rs27038 SNP indicated significantly increased mRNA and serum concentration levels for both cytokines. CONCLUSIONS: This study demonstrated the association of ERAP1 gene rs27038 polymorphism with the risk of AS in an Iranian population. Additionally, it seems that rs27038 is involved in the modulation of the inflammatory IL-17/IL-23 axis in AS.


Assuntos
Aminopeptidases/genética , Mediadores da Inflamação/sangue , Interleucina-17/sangue , Interleucina-23/sangue , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Homozigoto , Humanos , Mediadores da Inflamação/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-23/genética , Interleucina-23/imunologia , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/imunologia
9.
World J Microbiol Biotechnol ; 35(3): 45, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30810891

RESUMO

Dysbiosis of intestinal microbiota and aberrant inflammatory responses in gastrointestinal mucosa plays important roles in the development of inflammatory bowel disease (IBD). The purpose of this study was to demonstrate the probiotic activity of Lactococcus lactis and the ability of TNF-α-binding by recombinant L. lactis bearing TNF-α-binding affibodies. Various concentrations of recombinant L. lactis were exposed to TNF-α and its binding measured by ELISA. Mucosal biopsies of patients with active IBD were incubated with various L. lactis strains or E. coli DH5α strain and concentrations of TNF-α, IL-23, and IL-10 in the supernatants determined by ELISA. Recombinant L. lactis, at 1 × 109 and 1 × 108 CFU/mL, bound 22.6% and 18.4%, respectively of TNF-α (p < 0.05). When IBD-mucosa was incubated with any L. lactis strain at 1 × 109 CFU/mL, levels of TNF-α and IL-23 were significantly decreased and that of IL-10 increased relative to that for the sterile culture. Opposite trends were observed with E. coli cultures. Recombinant L. lactis at 1 × 108 CFU/mL bound as much as 62.8% (p = 0.026) of TNF-α in IBD-mucosa supernatants compared with the control strain. L. lactis strains are reported, for the first time, to induce an ex vivo anti-inflammatory cytokine profile in IBD inflamed mucosa. L. lactis could therefore constitute a promising alternative approach for treating IBD.


Assuntos
Anti-Inflamatórios/metabolismo , Citocinas/metabolismo , Engenharia Genética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/microbiologia , Lactococcus lactis/genética , Lactococcus lactis/metabolismo , Probióticos/farmacologia , Adolescente , Anti-Inflamatórios/uso terapêutico , Criança , Citocinas/genética , Citocinas/uso terapêutico , Disbiose , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Microbioma Gastrointestinal , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Masculino , Proteínas Recombinantes/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/uso terapêutico , Adulto Jovem
10.
Acta Derm Venereol ; 99(3): 298-303, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30460374

RESUMO

The Janus kinase 1/3 inhibitor tofacitinib has demonstrated an antipruritic effect in two phase III studies in psoriasis. However, the mechanisms behind this antipruritic effect are still unknown. We presently investigated whether tofacitinib affects spontaneous itch as well as expression of itch-related cytokines and epidermal nerve fiber density (ENFD) in the imiquimod-induced mouse model of psoriasis. Psoriasis-like skin lesions were produced by daily topical application of imiquimod to the back skin. Imiquimod treatment resulted in spontaneous scratching, which was significantly inhibited by tofacitinib treatment. Imiquimod treatment significantly increased mRNA expression of Il22, Il23, and Il31, reduced peptidergic ENFD, and increased nonpeptidergic ENFD compared to naive mice. Tofacitinib significantly decreased the expression of those cytokines and increased peptidergic ENFD without a significant effect on nonpeptidergic ENFD. Tofacitinib may inhibit psoriatic itch through inhibition of cytokine expression as well as modulation of epidermal innervation.


Assuntos
Antipruriginosos/farmacologia , Inibidores de Janus Quinases/farmacologia , Piperidinas/farmacologia , Prurido/prevenção & controle , Psoríase/tratamento farmacológico , Pirimidinas/farmacologia , Pirróis/farmacologia , Pele/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Imiquimode , Interleucina-23/genética , Interleucina-23/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Prurido/induzido quimicamente , Prurido/enzimologia , Prurido/psicologia , Psoríase/induzido quimicamente , Psoríase/enzimologia , Psoríase/psicologia , Pele/enzimologia , Pele/inervação
11.
Immunol Cell Biol ; 97(1): 29-38, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107066

RESUMO

BPSM1 (Bone phenotype spontaneous mutant 1) mice develop severe polyarthritis and heart valve disease as a result of a spontaneous mutation in the Tnf gene. In these mice, the insertion of a retrotransposon in the 3' untranslated region of Tnf causes a large increase in the expression of the cytokine. We have found that these mice also develop inducible bronchus-associated lymphoid tissue (iBALT), as well as nodular lymphoid hyperplasia (NLH) in the bone marrow. Loss of TNFR1 prevents the development of both types of follicles, but deficiency of TNFR1 in the hematopoietic compartment only prevents the iBALT and not the NLH phenotype. We show that the development of arthritis and heart valve disease does not depend on the presence of the tertiary lymphoid tissues. Interestingly, while loss of IL-17 or IL-23 limits iBALT and NLH development to some extent, it has no effect on polyarthritis or heart valve disease in BPSM1 mice.


Assuntos
Tecido Linfoide/patologia , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Medula Óssea/patologia , Hiperplasia , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Tecido Linfoide/metabolismo , Camundongos , Fator de Necrose Tumoral alfa/genética
12.
Sci Immunol ; 3(30)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30578351

RESUMO

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αß T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rß2-deficient than IL-12Rß1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.


Assuntos
Imunidade Inata/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Infecções por Micobactéria não Tuberculosa/imunologia , Mycobacterium/imunologia , Humanos , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-23/deficiência , Interleucina-23/genética , Linhagem
13.
Iran J Allergy Asthma Immunol ; 17(4): 298-307, 2018 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-30537793

RESUMO

Cytokines have prominent roles in activating of different T cells and shifting the immune response, in this study the role of three cytokines (IL-21, IL-23 and IL-27) is investigated in the liver transplant rejection. Three EDTA-treated blood samples were collected from each liver transplanted patient in 1st, 4th and 7th day of post-transplantation. The expression level of the mentioned cytokines was determined using real-time PCR for all samples. Also, the serum levels of cytokines were determined using ELISA tests. In acute rejection (AR) group (51 patients), mRNA expression pattern of IL-21and IL-23 showed a steady increase, but this pattern was converse for IL-27. Our results in non-acute rejection (non-AR) group (54 patients) showed an elevation in day 4 and then a decrease in day 7 for IL-21 and IL-23 genes. This pattern was converse again for IL-27 gene. In comparison between the two groups, in all 3 sampling times the mean of mRNA expression level of IL-21 and IL-23, showed an increase in AR group which this increase was significant for IL-21 in the 3rd (p=0.007) and for IL-23 in 2nd (p=0.048) and 3rd (p=0.049) sampling time, but the pattern of mRNA expression for IL-27 was contrary to the results of IL-21 and IL-23. Furthermore, ELISA technique also, showed the serum level changes the same as cytokines. In this study IL-21 and IL-23 showed pro-inflammatory properties in the liver transplant rejected patients. Also, IL-27 having different expression pattern, showed anti-inflammatory behavior which needs more considerations in future.


Assuntos
Rejeição de Enxerto/imunologia , Inflamação/imunologia , Interleucina-23/sangue , Interleucina-27/sangue , Interleucinas/sangue , Transplante de Fígado , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interleucina-23/genética , Interleucina-27/genética , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Estudos Retrospectivos , Adulto Jovem
14.
J Immunol ; 201(11): 3184-3198, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30404815

RESUMO

Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9-induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9-induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b-9-mediated IL-23 and IL-36a production of Thy-1N rats.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Interleucina-23/metabolismo , Interleucinas/metabolismo , Rim/metabolismo , Células Mesangiais/metabolismo , Nefrite/imunologia , Acetilação , Animais , Linhagem Celular , Humanos , Interleucina-23/genética , Interleucinas/genética , Rim/patologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Células Mesangiais/patologia , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Antígenos Thy-1/metabolismo , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismo
15.
Rheumatology (Oxford) ; 57(suppl_6): vi4-vi9, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445483

RESUMO

AS is a common rheumatic condition characterized by inflammation and new bone formation. The pathogenesis of AS is likely multifactorial and has not been fully elucidated to date. A major genetic role has been demonstrated. The strongest genetic association is with HLA B27. Numerous other associated genetic polymorphisms have been identified, including those affecting the type 17 immune pathway, although the precise link between genetics and pathogenesis remains unexplained. Several immunological alterations, together with recent therapeutic advances, support a central role for IL-23- and IL-17-producing immune cells in disease pathogenesis. Recently, perturbations of gut microbiota of AS patients have further catalysed research and offer potential for future therapeutic intervention. In this review we outline the genetic basis of AS and describe the current hypotheses for disease pathogenesis. We synthesize recent experimental research data and clinical studies to support a central role for the type 17/23 immune axis in AS.


Assuntos
Predisposição Genética para Doença/genética , Espondilite Anquilosante/genética , Microbioma Gastrointestinal , Antígeno HLA-B27/genética , Humanos , Interleucina-17/genética , Interleucina-23/genética , Polimorfismo Genético , Espondilite Anquilosante/microbiologia
16.
Front Immunol ; 9: 2641, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30487798

RESUMO

Objective: Despite extensive studies, the precise mechanism underlying spondyloarthritis, especially ankylosing spondylitis, remains elusive. This study aimed to develop an ideal animal model for an insight into mechanism of spondyloarthritis and functional relevance of SOCS3 in spondyloarthritis. Methods: Since SOCS3 is a major regulator of IL23-STAT3 signaling, we generated SOCS3 knockdown transgenic (TG) mice for development of an animal model of spondyloarthritis. A hydrodynamic delivery method was employed to deliver minicircle DNA expressing IL23 (mc-IL23) into wild-type (WT) and the TG mice. Knockdown/overexpression systems mediated by lentivirus and retrovirus were used to determine whether SOCS3 regulated osteoblast differentiation. Results: Forced expression of IL23 induced severe joint destruction and extensive bone loss in SOCS3 knockdown TG mice, while this treatment only caused moderate symptoms in WT mice. Furthermore, severe spondyloarthritis was found in IL23-injected TG mice as compared to mild disease observed in WT controls under same condition. Moreover, our studies showed that IL23 promoted osteoblast differentiation via activation of STAT3 pathway and disruption of SOCS3 expression greatly increased phosphorylation of STAT3. In addition, silencing SOCS3 resulted in enhanced osteoblast differentiation through activation of Smad1/5/9 signaling, as evidenced by elevated phosphorylation level of Smad1/5/9. Experiments further demonstrated that SOCS3 interacted with Smad1 and thus suppressed the BMP2-Smad signaling. Conclusions: The results reveal that SOCS3 is involved in IL23-induced spondyloarthritis and acts as a key regulator of osteoblast differentiation, and suggest that SOCS3 knockdown TG mice may be an ideal animal model for further studies of spondyloarthritis.


Assuntos
Diferenciação Celular , Interleucina-23 , Osteoblastos , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , DNA Circular/efeitos adversos , DNA Circular/genética , DNA Circular/imunologia , DNA Circular/farmacologia , Modelos Animais de Doenças , Inativação Gênica , Interleucina-23/efeitos adversos , Interleucina-23/genética , Interleucina-23/imunologia , Camundongos , Camundongos Knockout , Osteoblastos/imunologia , Osteoblastos/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/imunologia
17.
Arthritis Res Ther ; 20(1): 259, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30463609

RESUMO

BACKGROUND: Interleukin (IL)-23 can facilitate the differentiation of IL-17-producing helper T cells (Th17). The IL-23/IL-17 axis is known to play a key role in the immunopathogenesis of ankylosing spondylitis (AS). We hypothesized that the expression of microRNAs (miRNAs, miRs) would be regulated by IL-23 and that these miRNAs could participate in the immunopathogenesis of AS. METHODS: Expression profiles of human miRNAs in K562 cells, cultured in the presence or absence of IL-23 for 3 days, were analyzed by microarray. Potentially aberrantly expressed miRNAs were validated using T-cell samples from 24 patients with AS and 16 control subjects. Next-generation sequencing (NGS) was conducted to search for gene expression and biological functions regulated by specific miRNAs in the IL-23-mediated signaling pathway. RESULTS: Initial analysis revealed that the expression levels of 12 miRNAs were significantly higher, whereas those of 4 miRNAs were significantly lower, in K562 cells after coculture with IL-23 for 3 days. Among these IL-23-regulated miRNAs, the expression levels of miR-29b-1-5p, miR-4449, miR-211-3p, miR-1914-3p, and miR-7114-5p were found to be higher in AS T cells. The transfection of miR-29b-1-5p mimic suppressed IL-23-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation in K562 cells. After NGS analysis and validation, we found that miR-29b-1-5p upregulated the expression of angiogenin, which was also upregulated in K562 cells after coculture with IL-23. Increased expression of miR-29b-1-5p or miR-211-3p could enhance interferon-γ expression. CONCLUSIONS: Among the miRNAs regulated by IL-23, expression levels of five miRNAs were increased in T cells from patients with AS. The transfection of miR-29b-1-5p mimic could inhibit the IL-23-mediated STAT3 phosphorylation and might play a role in negative feedback control in the immunopathogenesis of AS.


Assuntos
Interleucina-23/biossíntese , MicroRNAs/biossíntese , Receptores de Interleucina/biossíntese , Espondilite Anquilosante/metabolismo , Linfócitos T/metabolismo , Adulto , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-23/genética , Células K562 , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Receptores de Interleucina/genética , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/genética
18.
J Exp Med ; 215(11): 2778-2795, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30282719

RESUMO

Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone marrow niches. In contrast, diurnal accumulation of neutrophils within the pulmonary vasculature influenced circadian transcription in the lungs. Neutrophil-influenced transcripts in this organ were associated with carcinogenesis and migration. Consistently, we found that neutrophils dictated the diurnal patterns of lung invasion by melanoma cells. Homeostatic infiltration of tissues unveils a facet of neutrophil biology that supports organ function, but can also instigate pathological states.


Assuntos
Neoplasias Pulmonares/imunologia , Pulmão/imunologia , Melanoma/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Animais , Feminino , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/imunologia , Interleucina-23/genética , Interleucina-23/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Knockout , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Neutrófilos/patologia , Transcrição Genética/imunologia
19.
Cell Physiol Biochem ; 50(3): 893-910, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30355939

RESUMO

BACKGROUND/AIMS: Vulvovaginal candidiasis (VVC) is a disease commonly occurring in sexually active women. The involvement of microRNAs in several kinds of infectious diseases has been highlighted in a number of researches. Therefore, we conducted the present study in order to investigate whether microRNA-1192 (miR-1192) would significantly target CXCR4 in Th17 cells as well as inflammatory factors in mouse models suffering from VVC. METHODS: Seventy-five mice were selected as test subjects for this study, of which twenty-five were used as the normal control, while the rest were treated with estradiol or oil-treated in order to establish VVC mouse models (each n = 25). Protein expressions of CXCR4, IL-6, IL-17, and IL-23 were all measured using both an immunohistochemistry and ELISA. The Th17 cell percentage in peripheral blood and the expression of RORγt in Th17 cells were detected using a flow cytometry. Mouse vaginal epithelial cells were isolated from normal mice, after which the mice were treated with estradiol to regulate their estrogen, followed by treatments involving the miR-1192 mimic, miR-1192 inhibitor, siRNA-CXCR4, and miR-1192 inhibitor + si-CXCR4. The cell cycle, apoptosis, and proliferation were all examined by using an additional flow cytometry as well as the employment of the MTT assay. The miR-1192, CXCR4, IL-6, IL-17, and IL-23 expressions in tissues and cells were both measured using both RT-qPCR and western blot assay techniques. RESULTS: The mice treated with either estradiol or oil had presented to us lowered levels in miR-1192 expression as well as higher levels in both Th17 cell percentage and expression of RORγt in Th17 cells, along with mRNA and protein expressions of CXCR4, IL-6, IL-17, and IL-23. In cell experiments, the mouse vaginal epithelial cells that had been treated with miR-1192 inhibitor had shown us a decreased cell proliferation rate and contrarily increased expressions of CXCR4, IL-6, IL-17, and IL-23 mRNA, protein, and cell apoptosis rate; these results were opposite to the ones found in the mice treated with miR-1192 mimic. CONCLUSION: Our results provided significant evidence that miR-1192 could directly development and progression of VVC by restraining the CXCR4 gene in the VVC mice.


Assuntos
Candidíase Vulvovaginal/patologia , MicroRNAs/metabolismo , Receptores CXCR4/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Apoptose , Candidíase Vulvovaginal/imunologia , Candidíase Vulvovaginal/microbiologia , Pontos de Checagem do Ciclo Celular , Modelos Animais de Doenças , Feminino , Interleucina-17/análise , Interleucina-17/química , Interleucina-17/metabolismo , Interleucina-23/análise , Interleucina-23/genética , Interleucina-23/metabolismo , Interleucina-6/análise , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Células Th17/citologia , Células Th17/metabolismo
20.
Front Immunol ; 9: 2262, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30333830

RESUMO

The immunomodulator Macrophage Migration Inhibitory Factor (MIF) exerts pleiotropic immunomodulatory activities and has been implicated in the pathogenesis of diverse inflammatory diseases. Expression levels of MIF are also significantly elevated in the skin and serum of psoriasis patients, but the pathogenic significance of MIF in psoriasis is unknown. We have therefore addressed the role of MIF in two mouse models of psoriasis, namely in the imiquimod-induced psoriasiform dermatitis (IIPD) and the IL-23-induced dermatitis model. Daily treatment with Aldara™ cream, containing imiquimod, markedly increased the abundance of MIF in the skin and generated a cellular skin expression pattern of MIF closely resembling that in human plaque psoriasis. Deficiency in MIF significantly alleviated IIPD. On the clinical level, all hallmarks of psoriasiform dermatitis, including erythema, skin infiltration, and desquamation were reduced in Mif -/- mice. On the histopathological level, MIF deficiency decreased keratinocyte hyperproliferation, inflammatory cell infiltration, specifically with respect to monocyte-derived cells, and dermal angiogenesis, suggesting that MIF may be involved in the pathogenesis of psoriasiform dermatitis through several mechanisms. Similarly, MIF deficiency also significantly reduced disease in the IL-23-induced dermatitis model, suggesting that MIF is involved in the pathogenic pathways activated by IL-23 and required to achieve full-blown psoriasiform dermatitis. Collectively, our results lend support to a possible disease-promoting role of MIF in psoriasis, which should be further investigated.


Assuntos
Dermatite/imunologia , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Psoríase/imunologia , Pele/imunologia , Animais , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Imiquimode/efeitos adversos , Imiquimode/farmacologia , Interleucina-23/genética , Interleucina-23/imunologia , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Camundongos , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/patologia , Pele/patologia
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