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1.
Nat Commun ; 10(1): 4121, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511508

RESUMO

The functionality of most secreted proteins depends on their assembly into a defined quaternary structure. Despite this, it remains unclear how cells discriminate unassembled proteins en route to the native state from misfolded ones that need to be degraded. Here we show how chaperones can regulate and control assembly of heterodimeric proteins, using interleukin 23 (IL-23) as a model. We find that the IL-23 α-subunit remains partially unstructured until assembly with its ß-subunit occurs and identify a major site of incomplete folding. Incomplete folding is recognized by different chaperones along the secretory pathway, realizing reliable assembly control by sequential checkpoints. Structural optimization of the chaperone recognition site allows it to bypass quality control checkpoints and provides a secretion-competent IL-23α subunit, which can still form functional heterodimeric IL-23. Thus, locally-restricted incomplete folding within single-domain proteins can be used to regulate and control their assembly.


Assuntos
Interleucina-23/metabolismo , Chaperonas Moleculares/metabolismo , Animais , Células COS , Cisteína/metabolismo , Retículo Endoplasmático/metabolismo , Meia-Vida , Humanos , Interleucina-23/química , Modelos Biológicos , Dobramento de Proteína , Estabilidade Proteica , Estrutura Secundária de Proteína
2.
Artigo em Inglês | MEDLINE | ID: mdl-31327402

RESUMO

The interleukin (IL)-12 family of cytokines, including IL12 and IL 23, play an important role in driving aberrant Th1 and Th17 immune responses in patients with Crohn's disease (CD). Targeting this pathway has opened new avenues for therapeutic intervention. The approval of ustekinumab, a monoclonal antibody blocking the common p40 subunit of IL12 and IL23, marked an important evolution in medical management for CD: this novel class of biologic therapy demonstrated efficacy in both patients naïve to biologics as well as in patients experiencing inadequate response or loss of response to TNF antagonists. However, as our understanding of the IL12/23 pathway has evolved, specific targeting of IL23 through its unique p19 subunit has become a focus for novel therapeutic development. IL23p19 antagonists have been shown in head-to-head trials to have superior efficacy to ustekinumab for other immune-mediated conditions such as psoriasis. In CD, phase II trials of monoclonal antibodies targeting IL23, including risankizumab and brazikumab, have shown promising results, with multiple agents now entering phase II or phase III studies. In this review, we summarize the current evidence for both anti-IL12/23p40 and anti-IL23p19 monoclonal antibodies in CD.


Assuntos
Doença de Crohn/terapia , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Doença de Crohn/patologia , Humanos
3.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295952

RESUMO

Innate immunity represents the semi-specific first line of defense and provides the initial host response to tissue injury, trauma, and pathogens. Innate immunity activates the adaptive immunity, and both act highly regulated together to establish and maintain tissue homeostasis. Any dysregulation of this interaction can result in chronic inflammation and autoimmunity and is thought to be a major underlying cause in the initiation and progression of highly prevalent immune-mediated inflammatory diseases (IMIDs) such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases among others, and periodontitis. Th1 and Th2 cells of the adaptive immune system are the major players in the pathogenesis of IMIDs. In addition, Th17 cells, their key cytokine IL-17, and IL-23 seem to play pivotal roles. This review aims to provide an overview of the current knowledge about the differentiation of Th17 cells and the role of the IL-17/IL-23 axis in the pathogenesis of IMIDs. Moreover, it aims to review the association of these IMIDs with periodontitis and briefly discusses the therapeutic potential of agents that modulate the IL-17/IL-23 axis.


Assuntos
Inflamação/imunologia , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Periodontite/etiologia , Periodontite/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Doenças Autoimunes/complicações , Autoimunidade , Diferenciação Celular , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Humanos , Imunomodulação , Mediadores da Inflamação/metabolismo , Periodontite/diagnóstico , Periodontite/terapia , Transdução de Sinais , Células Th17/citologia
4.
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
5.
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
6.
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
7.
Int J Oncol ; 54(6): 2200-2210, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081048

RESUMO

Helicobacter pylori (HP) is a pathogenic bacterium associated with chronic gastritis, gastric ulcer and gastric cancer. In the present study, the primary carcinogenesis process of normal gastric epithelial cells (GES­1) infected with HP was investigated. It was determined that infected gastric mucosal epithelial GES­1 cells secreted increased interleukin­8 (IL­8) and IL­23, and exhibited enhanced expression of inducible nitric oxide synthase and cyclooxygenase­2, inducing inflammatory reactions and resulting in apoptosis. The bacterial infection significantly increased the expression of carcinogenesis­associated genes, including p16, c­Myc, p53 and p21, as well as the expression of cell surface signaling molecules cluster of differentiation 44 (CD44) and CD54 in GES­1 cells or tissues of patients with gastritis and gastric cancer in vitro or in vivo. Simultaneously, the migration and invasion abilities of normal gastric epithelial GES­1 cells were increased following HP infection. These observations demonstrated that the inflammatory response of HP infection could cause normal gastric epithelial cells to undergo significant cancerous reactions, indicating that HP is a risk factor for gastric cancer.


Assuntos
Infecções por Helicobacter/complicações , Helicobacter pylori/imunologia , Neoplasias Gástricas/microbiologia , Estômago/citologia , Linhagem Celular , Movimento Celular , Células Epiteliais/citologia , Células Epiteliais/microbiologia , Infecções por Helicobacter/imunologia , Humanos , Interleucina-23/metabolismo , Interleucina-8/metabolismo , Invasividade Neoplásica , Óxido Nítrico Sintase Tipo II/metabolismo , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/imunologia
8.
Drugs ; 79(8): 893-900, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31098898

RESUMO

Risankizumab (Skyrizi®), a humanised IgG monoclonal antibody that targets the p19 subunit of IL-23, was developed by AbbVie in collaboration with Boehringer Ingelheim for the treatment of immunological and inflammatory disorders. In March 2019, risankizumab received its first global approval in Japan for the treatment of adults with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis and erythrodermic psoriasis. Risankizumab has also received approval in the USA, Canada and the EU for the treatment of moderate-to-severe plaque psoriasis, and is in phase 3 development for this indication as well as psoriatic arthritis in several countries worldwide. Phase 2 and 3 clinical evaluation of risankizumab is ongoing in several countries in the treatment of Crohn's disease and ulcerative colitis. Risankizumab is also in phase 2 development for the treatment of atopic dermatitis globally. This article summarizes the milestones in the development of risankizumab leading to this first approval for psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis and erythrodermic psoriasis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Psoríase/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Artrite Psoriásica/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Aprovação de Drogas , Humanos , Interleucina-23/metabolismo , Índice de Gravidade de Doença
9.
Nat Commun ; 10(1): 2162, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089134

RESUMO

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1ß, IL-23 and TGF-ß. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents.


Assuntos
Plasticidade Celular/imunologia , Fibrose Cística/imunologia , Inflamação/imunologia , Pólipos Nasais/imunologia , Células Th17/imunologia , Adulto , Animais , Linhagem Celular , Fibrose Cística/sangue , Fibrose Cística/patologia , Feminino , Humanos , Imunidade Inata , Inflamação/sangue , Inflamação/patologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Pólipos Nasais/sangue , Pólipos Nasais/patologia , Neutrófilos/imunologia , Adulto Jovem
10.
Endocr J ; 66(5): 423-430, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30814438

RESUMO

T helper (Th) 17 cells and interleukin (IL)-17 play a significant role in the pathogenesis of autoimmune thyroid disease (AITD). However, it has recently become clear that Th17 cells are more heterogeneous and exhibit two different phenotypes, whereas IL-23 and IL-1ß are crucial for the generation of pathogenic Th17 lymphocytes. We aimed to investigate the association between IL-17 and Th17-promoting cytokines in AITD by studying the immunoexpression patterns of IL-17, IL-23, and IL-1ß in thyroid tissue. Following thyroidectomy, 29 patients with AITD (21 cases of Hashimoto's thyroiditis (HT) and 8 cases of Graves' disease (GD)) and 18 patients with colloid goiter, as controls, were enrolled in this study, and immunohistochemistry was performed. The expression level of IL-17 in thyrocytes was significantly higher in HT and GD patients than in colloid goiter patients. Immunopositivity for both IL-23 and IL-1ß was significantly increased in HT patients compared to GD and colloid goiter patients. However, no difference was found between IL-23 or IL-1ß expression in patients with GD and colloid goiter. A positive correlation between IL-17 and IL-23 as well as IL-17 and IL-1ß expression was observed in HT patients (r = 0.574, p = 0.007 and r = 0.461, p = 0.036, respectively). In the GD group, IL-17 was positively correlated with IL-1ß (r = 0.817, p = 0.013) but not with IL-23 expression. We found increased IL-23 and IL-1ß expression in the HT group but not in the GD group. Furthermore, both interleukins were correlated with IL-17 immunopositivity in thyroid tissue, suggesting that pathogenic Th17-promoting cytokines may play a role in HT pathogenesis.


Assuntos
Doença de Graves/metabolismo , Doença de Hashimoto/metabolismo , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Células Th17/metabolismo , Adulto , Idoso , Feminino , Bócio/metabolismo , Bócio/cirurgia , Doença de Graves/cirurgia , Doença de Hashimoto/cirurgia , Humanos , Imuno-Histoquímica , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Células Epiteliais da Tireoide/metabolismo , Tireoidectomia
11.
Cells ; 8(3)2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917537

RESUMO

Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways.


Assuntos
Predisposição Genética para Doença , Interleucinas/metabolismo , Linfócitos/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Adulto , Alelos , Estudos de Casos e Controles , Apresentação Cruzada/imunologia , Feminino , Humanos , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Fatores de Risco
12.
mBio ; 10(2)2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890606

RESUMO

The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3+) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-ß expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites.IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.


Assuntos
Proteínas de Bactérias/metabolismo , Diferenciação Celular , Mucosa Gástrica/patologia , Helicobacter pylori/imunologia , Membrana Mucosa/patologia , Células Mieloides/efeitos dos fármacos , Linfócitos T Reguladores/fisiologia , Animais , Células Dendríticas/imunologia , Modelos Animais de Doenças , Infecções por Helicobacter/patologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/metabolismo , Evasão da Resposta Imune , Interleucina-10/metabolismo , Interleucina-23/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Camundongos , Fator de Crescimento Transformador beta/metabolismo
13.
Ital J Pediatr ; 45(1): 41, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30922377

RESUMO

BACKGROUND: Vitamin D plays an important role in inflammatory responses after antigen exposure. Interleukin-23 (Il-23) promotes Il-17-dependent inflammation during Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection. We aimed to compare the ability of calcitriol and cholecalciferol to modulate the inflammatory response of the CF airways infected with P. aeruginosa. METHODS: This was a randomized, placebo-controlled, double-blind, cross-over trial. Twenty-three patients with CF (aged 6-19), chronically infected by P. aeruginosa were randomly assigned to: calcitriol group receiving 1,25(OH)2D 0,5 mcg daily or cholecalciferol group receiving cholecalciferol 1000 IU daily for three months. The levels of Il-23 and Il-17A in the exhaled breath concentrate (EBC) were measured. Calcium-phosphorus balance was also evaluated (serum concentration of calcium, phosphorus, 25OHD, parathormone (PTH) and calcium/creatinine ratio in urine). Data were analyzed using means of Stata/Special Edition, release 14.2. A level of P < 0.05 was considered statistically significant. RESULTS: The level of Il-17A in EBC significantly decreased in calcitriol group from 0,475 pg/mL (± SD 0,515 pg/mL) to 0,384 pg/mL (± SD 0,429 pg/mL) (p = 0,008); there was no change in cholecalciferol group (p = 0,074). The level of Il-23 in EBC did not significantly change in calcitriol group (p = 0,086); there was significant decrease in cholecalciferol group from 8,90 pg/mL (± SD 4,07 pg/mL) to 7,33 pg/mL (± SD 3,88 pg/mL) (p = 0,001). In calcitriol group serum phosphorus and PTH significantly decreased (p = 0,021 and p = 0,019 respectively), the concentration of calcium significantly increased (p = 0,001); there were no changes in cholecalciferol group. CONCLUSIONS: Both analogs of vitamin D revealed their anti-inflammatory effect and reduced the level of Il-17A and Il-23 in the airway of CF patients with chronic P. aeruginosa infection. We observed improvement in calcium-phosphorus metabolism after supplementation with calcitriol, without adverse effects. It is recommended to use vitamin D in CF patients.


Assuntos
Calcitriol/farmacologia , Colecalciferol/farmacologia , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Pulmão/metabolismo , Pneumonia Bacteriana/microbiologia , Adolescente , Testes Respiratórios , Cálcio/sangue , Cálcio/urina , Criança , Creatinina/urina , Estudos Cross-Over , Fibrose Cística/metabolismo , Método Duplo-Cego , Humanos , Masculino , Hormônio Paratireóideo/sangue , Fósforo/sangue , Projetos Piloto , Infecções por Pseudomonas/complicações , Pseudomonas aeruginosa , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitaminas/farmacologia , Adulto Jovem
14.
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
15.
Cell ; 176(5): 998-1013.e16, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30712876

RESUMO

Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1ß and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumor development and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer intervention.


Assuntos
Interações entre Hospedeiro e Microrganismos/imunologia , Linfócitos Intraepiteliais/imunologia , Neoplasias Pulmonares/imunologia , Animais , Proliferação de Células , Feminino , Interleucina-17/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/fisiologia , Pulmão/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta , Simbiose/imunologia , Linfócitos T/imunologia
16.
Front Immunol ; 10: 44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740104

RESUMO

TYK2 is a JAK family member that functions downstream of multiple cytokine receptors. Genome wide association studies have linked a SNP (rs34536443) within TYK2 encoding a Proline to Alanine substitution at amino acid 1104, to protection from multiple autoimmune diseases including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The protective role of this SNP in autoimmune pathogenesis, however, remains incompletely understood. Here we found that T follicular helper (Tfh) cells, switched memory B cells, and IFNAR signaling were decreased in healthy individuals that expressed the protective variant TYK2 A1104 (TYK2 P ). To study this variant in vivo, we developed a knock-in murine model of this allele. Murine Tyk2 P expressing T cells homozygous for the protective allele, but not cells heterozygous for this change, manifest decreased IL-12 receptor signaling, important for Tfh lineage commitment. Further, homozygous Tyk2 P T cells exhibited diminished in vitro Th1 skewing. Surprisingly, despite these signaling changes, in vivo formation of Tfh and GC B cells was unaffected in two models of T cell dependent immune responses and in two alternative SLE models. TYK2 is also activated downstream of IL-23 receptor engagement. Here, we found that Tyk2 P expressing T cells had reduced IL-23 dependent signaling as well as a diminished ability to skew toward Th17 in vitro. Consistent with these findings, homozygous, but not heterozygous, Tyk2 P mice were fully protected in a murine model of MS. Homozygous Tyk2 P mice had fewer infiltrating CD4+ T cells within the CNS. Most strikingly, homozygous mice had a decreased proportion of IL-17+/IFNγ+, double positive, pathogenic CD4+ T cells in both the draining lymph nodes (LN) and CNS. Thus, in an autoimmune model, such as EAE, impacted by both altered Th1 and Th17 signaling, the Tyk2 P allele can effectively shield animals from disease. Taken together, our findings suggest that TYK2P diminishes IL-12, IL-23, and IFN I signaling and that its protective effect is most likely manifest in the setting of autoimmune triggers that concurrently dysregulate at least two of these important signaling cascades.


Assuntos
Autoimunidade/imunologia , TYK2 Quinase/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Adulto , Animais , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Técnicas de Introdução de Genes , Humanos , Interferon Tipo I/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-12/metabolismo , TYK2 Quinase/genética , Adulto Jovem
18.
Mucosal Immunol ; 12(3): 612-623, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30765845

RESUMO

Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn's disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL)-23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model. This inhibition of IL-23 expression is associated with elevated autophagy activity. Ablating the autophagy gene Atg7 increases the expression of IL-23, leading to increased expression of IL-22 and increased fibrosis. Both induction of IL-22 and intestinal fibrosis occurred in RAG-/- mice and depletion of innate lymphoid cells (ILCs) attenuates the fibrotic reaction, suggesting that the pro-fibrotic process is independent of T and B cells. Moreover, IL-22 facilitates the transformation of fibroblasts into myofibroblasts. Finally, the fibrotic reaction was attenuated upon neutralization of either IL-23 or IL-22. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which altered mTOR/autophagy in CX3Cr1+ mononuclear phagocytes up-regulates the IL-23/IL-22 axis, leading to an excessive fibrotic response. Thus, our findings suggest that this cascade could be a therapeutic target for alleviation of CD fibrosis.


Assuntos
Doença de Crohn/imunologia , Interleucina-23/metabolismo , Interleucinas/metabolismo , Intestinos/patologia , Fagócitos/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Imunidade Inata , Interleucina-23/imunologia , Interleucinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
19.
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
20.
Cell Biol Int ; 43(3): 313-322, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30632648

RESUMO

The functional and physical interaction between mitochondria and the endoplasmic reticulum (ER) has been the subject of intense study. To test the effect of this interaction on macrophage inflammatory activation, the human macrophage-like monocytic leukemia cell line THP-1 was treated with oligomycin, rotenone, or sodium azide, which induce mitochondrial dysfunction (MD) by blocking the electron transport chain (ETC). MD induced by these agents triggered activation of various sensors and markers of ER stress. This linkage affected macrophage function since LPS-induced expression of IL-23 was enhanced by the MD inducers, and this enhancing effect was abolished by inhibition of pancreatic endoplasmic reticulum kinase (PERK) activity. This MD-mediated ER stress may be universal since it was observed in human embryonic kidney HEK293 cells and colon cancer SW480 cells. On the other hand, MD regulated LPS-induced activation of the AKT/GSK3ß/ß-catenin pathway in a manner not affected by inhibition of PERK or inositol-requiring enzyme 1α (IRE1α) activities. These results indicate that the occurrence of MD can lead to ER stress and these two events, separately or in combination, can affect various cellular processes.


Assuntos
Estresse do Retículo Endoplasmático , Mediadores da Inflamação/metabolismo , Mitocôndrias/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Humanos , Interleucina-23/metabolismo , Lipopolissacarídeos/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Fator de Transcrição CHOP/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , beta Catenina/metabolismo
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