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1.
Nat Commun ; 10(1): 4246, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534137

RESUMO

Allergic asthma is an inflammatory disorder of the airway without satisfactory traditional therapies capable of controlling the underlying pathology. New approaches that can overcome the detrimental effects of immune dysregulation are thus desirable. Here we adoptively transfer ovalbumin (OVA) peptide-primed CD4-CD8- double negative T (DNT) cells intravenously into a mouse model of OVA-induced allergic asthma to find that OVA-induced airway hyperresponsiveness, lung inflammation, mucus production and OVA-specific IgG/IgE production are significantly suppressed. The immunosuppressive function of the OVA-specific DNT cells is dependent on the inhibition of CD11b+ dendritic cell function, T follicular helper cell proliferation, and IL-21 production. Mechanistically, Lag3 contributes to MHC-II antigen recognition and trogocytosis, thereby modulating the antigen-specific immune regulation by DNT cells. The effectiveness of ex vivo-generated allergen-specific DNT cells in alleviating airway inflammation thus supports the potential utilization of DNT cell-based therapy for the treatment of allergic asthma.


Assuntos
Antígenos CD/metabolismo , Asma/fisiopatologia , Asma/terapia , Hiper-Reatividade Brônquica/imunologia , Linfócitos T Reguladores/transplante , Células Th2/imunologia , Transferência Adotiva , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/terapia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe II , Imunoglobulina E/biossíntese , Imunoglobulina G/biossíntese , Interleucinas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Linfócitos T Reguladores/imunologia
2.
Presse Med ; 48(9): 919-930, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31543394

RESUMO

Giant cell arteritis (GCA) is a large-vessel vasculitis involving the aorta and its main branches, especially supra aortic branches. Although much progress has been made, the pathophysiology remains incompletely understood. An initial trigger, suspected of infectious origin, lead to the maturation and recruitment of dendritic cells (DC). The lack of migration of these DC allows the local recruitment of T-lymphocytes (LT). These LT- CD4+ polarize in Type 1 helper (Th1), Th17 but also Th9. A qualitative and quantitative deficit in regulatory T cells (Treg) is observed under the influence of IL-21 overproduction. In addition, an imbalance in the Th17/Treg balance is favored by IL-6. The secretion of IFN-γ, IL-17, IL-6, IL-33 is responsible for a sustained local inflammatory reaction that is organized around tertiary lymphoid follicles. Locally recruited macrophages secrete reactive forms of oxygen together with VEGF and PDGF. These growth factors, together with neurotrophins and endothelin contribute to increase the proliferation of vascular smooth muscle cells (VSMCs). The imbalance between matrix metalloproteases (MMP)-2, MMP-9 and MMP-14 and tissue inhibitors of metalloproteases (TIMP)-1 and TIMP-2 also contribute to the remodeling process occurring in the vessel wall. Finally, arterial neovascularization contribute to the perpetuation of lymphocyte recruitment. This persistent remodeling is sometimes complicated by ischemic events responsible for the initial severity of the disease.


Assuntos
Arterite de Células Gigantes/fisiopatologia , Remodelação Vascular/fisiologia , Animais , Linfócitos B/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Proliferação de Células , Células Dendríticas/fisiologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/etiologia , Arterite de Células Gigantes/patologia , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucina-6/fisiologia , Interleucinas/biossíntese , Ativação Linfocitária/fisiologia , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , Músculo Liso Vascular/patologia , Neovascularização Patológica/fisiopatologia , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia
3.
Biosci Biotechnol Biochem ; 83(12): 2298-2306, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448678

RESUMO

Lactic acid bacteria are known to have various health-promoting effects and are highly expected to find applications in anti-allergic food materials. In this study, we focused on Lactobacillus helveticus SBT2171 (LH2171), which reportedly modifies some unique immune responses and ameliorated symptoms of patients allergic to mites and house dust in the previous studies. We examined the effect of LH2171 on cytokine production by antigen-stimulated murine naïve splenocytes in vitro and demonstrated that it inhibited IL-4 and IL-13 production while enhancing IFN-γ and IL-10 production. Then, we examined the anti-allergic effect of LH2171 in vivo using a murine model of pollen allergy and found that LH2171 reduced the sneezing frequency when orally administered to mice. We successfully confirmed the immune modulatory activity of LH2171 and its anti-allergic activity against inhaled antigens. These evidences would contribute to identifying the anti-allergic mechanism of LH2171.Abbreviations: ALDH: aldehyde dehydrogenase; EGCG: epigallocatechin gallate; LAB: lactic acid bacteria; LH2171: Lactobacillus helveticus SBT2171; NALT: nasal-associated lymphoid tissue; OVA: ovalbumin.


Assuntos
Lactobacillus helveticus , Rinite Alérgica Sazonal/prevenção & controle , Administração Oral , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Imunoglobulina E/biossíntese , Imunoglobulina E/imunologia , Interferon gama/biossíntese , Interleucinas/antagonistas & inibidores , Interleucinas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/metabolismo
4.
Eur J Med Res ; 24(1): 24, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331400

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T-cell-dependent B-cell activation and altered T-cell response. Co-stimulatory and co-inhibitory molecules regulate and exert T-cell differentiation, survival and cytokine production. CD134+ and PD-1+ T-cells in SLE patients are increased in SLE. The aim of this study was to characterize CD134+ and PD-1+CD4+ T-cells according to their ability to produce IFN-γ, IL-21 and IL-22 in SLE patients. METHODS: Peripheral blood of 39 SLE patients and 19 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) calcium ionophore (Ca-Io). The expression of IFN-γ, IL-21 and IL-22 T-cells within the CD134+ and PD-1+ T-cells was analyzed by flow cytometry. Disease activity was assessed by SLE Disease Activity Index. RESULTS: Peripheral unstimulated CD134+ and PD-1+ CD4+ T-cells were significantly increased in patients with lupus nephritis. Upon stimulation both, CD134+ and PD-1+ CD4+ T-cells, produced significantly less IFN-γ in SLE patients as compared to HC. The percentages of IL-22 within the CD134+CD4+ T-cells were also significantly decreased in SLE as compared to HC. CONCLUSION: CD134+ and PD-1+CD4+ T-cells have mainly a Th1 effector T-cell signature. A lower proportion produces also IL-21 and IL-22. The impaired capacity to produce IFN-γ and IL-22 in SLE patients may contribute to the pathogenesis of the disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucinas/biossíntese , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ionóforos de Cálcio/farmacologia , Estudos de Casos e Controles , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Interferon gama/metabolismo , Interleucinas/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/imunologia , Masculino , Acetato de Tetradecanoilforbol/farmacologia
5.
Medicine (Baltimore) ; 98(30): e16610, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348308

RESUMO

The purpose of this study was to investigate the influences of varied anesthetic methods and depths on inflammatory cytokines and stress hormone levels in radical operation among colon cancer patients during perioperative period.A total of 120 patients were collected in the study and randomly divided into 4 groups, A: general anesthesia + Narcotrend D1, B: general anesthesia + Narcotrend D2, C: general anesthesia + epidural anesthesia + Narcotrend D1, D: general anesthesia + epidural anesthesia + Narcotrend D2. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, cortisol (Cor), adrenocorticotropic hormone (ACTH), and endothelin-1 (ET-1) were measured adopting commercial kits before anesthesia (T0), 4 hours after surgery (T1), 24 hours after surgery (T2), and 72 hours after surgery (T3).There was no significant difference in basic clinical characteristics among the groups. In comparison with group A, B and C, group D showed significantly lower levels of TNF-α, IL-6, IL-10, Cor, ACTH, and ET-1 at T1 and T2 (all, P < .05). Significantly higher levels of TNF-α, IL-6, IL-10, Cor, and ACTH were detected at T1 and T2 than those at T0 (all, P < .05), whereas, at T3, the levels of inflammatory cytokines and stress hormones were all decreased near to preoperation ones.General anesthesia combined with epidural anesthesia at Narcotrend D2 depth plays an important role in reducing immune and stress response in patients with colon cancer from surgery to 24 hours after surgery.


Assuntos
Anestesia Epidural/métodos , Anestesia Geral/métodos , Neoplasias do Colo/cirurgia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Hormônio Adrenocorticotrópico/biossíntese , Citocinas/sangue , Quimioterapia Combinada , Endotelina-1/biossíntese , Feminino , Humanos , Hidrocortisona/biossíntese , Mediadores da Inflamação/sangue , Interleucinas/biossíntese , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/biossíntese
6.
Br J Cancer ; 120(9): 903-912, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30956278

RESUMO

BACKGROUND: The immunosuppressive role of the cytokine IL-35 in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, we analysed the localisation and regulation of IL-35 in the lung of patients with non-small cell lung cancer (NSCLC) to further elucidate the immune-escape of cancer cells in perioperative course of disease. METHODS: Interleukin 35 (IL-35) was measured by ELISA in postoperative serum from 7 patients with NSCLC as well as 8 samples from healthy controls. Immunohistochemistry, FACS analysis, real-time PCR, as well as western blot from samples of the control (CTR), peri-tumoural (PT) and the tumoural (TU) region of the lung derived from patients with NSCLC and 10 controls were performed. RESULTS: Here we found elevated levels of IL-35 in the TU region as well as postoperative serum from patients with lung adenocarcinoma. Consistently, we found an increased expression of IL-35+Foxp-3+ cells, which associated with ARG1 mRNA expression and decreased TNFA in the TU region of the lung of patients with NSCLC as compared to their CTR region. Furthermore, in the CTR region of the lung of patients with NSCLC, CD68+ macrophages were induced and correlated with IL-35+ cells. Finally, IL-35 positively correlated with TTF-1+PD-L1+ cells in the TU region of NSCLC patients. CONCLUSIONS: Induced IL-35+Foxp3+ cell numbers in the TU region of the lung of patients with NSCLC associated with ARG1 mRNA expression and with TTF-1+PD-L1+ cells. In the tumour-free CTR area, IL-35 correlated with CD68+ macrophages. Thus inhibitors to IL-35 would probably succeed in combination with antibodies against immune checkpoints like PD-L1 and PD-1 currently used against NSCLC because they would inhibit immunosuppressive macrophages and T regulatory cells while promoting T cell-mediated anti-tumoural immune responses in the microenvironment as well as the TU region of NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Interleucinas/imunologia , Neoplasias Pulmonares/imunologia , Células A549 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Estudos de Casos e Controles , Citometria de Fluxo , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/imunologia , Humanos , Imuno-Histoquímica , Subunidade p35 da Interleucina-12/biossíntese , Subunidade p35 da Interleucina-12/genética , Subunidade p35 da Interleucina-12/imunologia , Interleucinas/biossíntese , Interleucinas/genética , Pulmão/imunologia , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Antígenos de Histocompatibilidade Menor/biossíntese , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Evasão Tumoral
7.
Circ Res ; 124(9): 1323-1336, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30832557

RESUMO

RATIONALE: Targeting inflammation has been shown to provide clinical benefit in the field of cardiovascular diseases. Although manipulating regulatory T-cell function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. IL (interleukin)-35, an immunosuppressive cytokine mainly produced by regulatory T cells, is a novel member of the IL-12 family and is composed of an EBI3 (Epstein-Barr virus-induced gene 3) subunit and a p35 subunit. However, the role of IL-35 in infarct healing remains elusive. OBJECTIVE: This study aimed to determine whether IL-35 signaling is involved in healing and cardiac remodeling after myocardial infarction (MI) and, if so, to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: IL-35 subunits (EBI3 and p35), which are mainly expressed in regulatory T cells, were upregulated in mice after MI. After IL-35 inhibition, mice showed impaired infarct healing and aggravated cardiac remodeling, as demonstrated by a significant increase in mortality because of cardiac rupture, decreased wall thickness, and worse cardiac function compared with wild-type MI mice. IL-35 inhibition also led to decreased expression of α-SMA (α-smooth muscle actin) and collagen I/III in the hearts of mice after MI. Pharmacological inhibition of IL-35 suppressed the accumulation of Ly6Clow and major histocompatibility complex IIlow/C-C motif chemokine receptor type 2- (MHC IIlow CCR2-) macrophages in infarcted hearts. IL-35 activated transcription of CX3CR1 (C-X3-C motif chemokine receptor 1) and TGF (transforming growth factor) ß1 in macrophages by inducing GP130 signaling, via IL12Rß2 and phosphorylation of STAT1 (signal transducer and activator of transcription family) and STAT4 and subsequently promoted Ly6Clow macrophage survival and extracellular matrix deposition. Moreover, compared with control MI mice, IL-35-treated MI mice showed increased expression of α-SMA and collagen within scars, correlating with decreased left ventricular rupture rates. CONCLUSIONS: IL-35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling after MI by promoting reparative CX3CR1+Ly6Clow macrophage survival.


Assuntos
Interleucinas/fisiologia , Macrófagos/fisiologia , Infarto do Miocárdio/fisiopatologia , Cicatrização/fisiologia , Transferência Adotiva , Animais , Anticorpos Monoclonais/farmacologia , Receptor 1 de Quimiocina CX3C/biossíntese , Receptor 1 de Quimiocina CX3C/genética , Sobrevivência Celular , Cicatriz/metabolismo , Proteínas da Matriz Extracelular/biossíntese , Regulação da Expressão Gênica/fisiologia , Ruptura Cardíaca Pós-Infarto/fisiopatologia , Ruptura Cardíaca Pós-Infarto/prevenção & controle , Interleucinas/antagonistas & inibidores , Interleucinas/biossíntese , Interleucinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/biossíntese , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Miocárdio/metabolismo , Receptores de Citocinas/antagonistas & inibidores , Receptores de Citocinas/biossíntese , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/genética , Regulação para Cima , Remodelação Ventricular/fisiologia
8.
Biochem Pharmacol ; 165: 240-248, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30885765

RESUMO

The four core members of the Interleukin-12 (IL-12) family of cytokines, IL-12, IL-23, IL-27 and IL-35 are heterodimers which share α- and ß-cytokine subunits. All four cytokines are immune modulators and have been proposed to play divergent roles in inflammatory arthritis. In recent years additional combinations of α- and ß-cytokine subunits belonging to the IL-12 family have been proposed to form novel cytokines such as IL-39. However, the actual extent of the combinatorial potential of the cytokine subunits in the human IL-12 family is not known. Here, we identify several combinations of subunits that form secreted heterodimeric assemblies based on a systematic orthogonal approach. The heterodimers are detected in the conditioned media harvested from mammalian cell cultures transfected with unfused pairs of cytokine subunits. While certain previously reported subunit combinations could not be recapitulated, our approach showed robustly that all four of the canonical members could be secreted. Furthermore, we provide evidence for the interaction between Cytokine Receptor Like Factor 1 (CRLF1) and Interleukin-12 subunit alpha (p35). Similar to IL-27 and IL-35 this novel heterodimer is not abundantly secreted rendering isolation from the conditioned medium very challenging, unlike IL-12 and IL-23. Our findings set the stage for fine-tuning approaches towards the biochemical reconstitution of IL-12 family cytokines for biochemical, cellular, and structural studies.


Assuntos
Interleucina-12/química , Interleucina-23/biossíntese , Interleucinas/química , Proteínas Recombinantes de Fusão/química , Células HEK293 , Humanos , Interleucina-12/biossíntese , Interleucina-23/química , Interleucinas/biossíntese , Multimerização Proteica , Subunidades Proteicas/biossíntese , Subunidades Proteicas/química , Proteínas Recombinantes de Fusão/biossíntese
9.
Nature ; 566(7743): 249-253, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700914

RESUMO

Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Colo/citologia , Interleucinas/farmacologia , Mutagênicos/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Neoplasias do Colo/prevenção & controle , Dano ao DNA , Dieta/efeitos adversos , Glucosinolatos/administração & dosagem , Glucosinolatos/farmacologia , Imunidade Inata , Interleucinas/biossíntese , Mucosa Intestinal/citologia , Ligantes , Camundongos , Mutagênicos/administração & dosagem , Mutação/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Interleucina/metabolismo , Células-Tronco/citologia , Linfócitos T/metabolismo
10.
Clin Exp Rheumatol ; 37(5): 820-825, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767867

RESUMO

OBJECTIVES: Angiogenesis in bone and osteogenesis appear to be closely linked, suggesting the existence of molecular crosstalk between pro-angiogenic molecules and osteoblasts. The pro-angiogenic molecules vascular endothelial growth factor (VEGF) with its receptors Flt-1, Flk-1 and fibroblast growth factor (FGF)-2 play a crucial role in born formation, an early and critical event in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-35 is demonstrated to be an anti-inflammatory cytokine in RA. However, the mechanisms involved are not fully understood. This study aims to investigate whether IL-35 has an impact on angiogenesis in osteoblasts and its related signalling pathway in RA. METHODS: The effects of IL-35 on osteoblasts proliferation, apoptosis and pro-angiogenic molecules mRNA and protein were examined using osteoblast-like MC3T3E1 cells in vitro. The effects of IL-35 on proliferation and apoptosis were examined using cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. Pro-angiogenic molecules expression were assessed by real time PCR and ELISA, respectively. The signalling pathway between IL-35, bone formation, angiogenesis and signalling pathway was also investigated. RESULTS: IL-35 promoted osteoblasts proliferation and inhibited apoptosis in a dose-dependent manner in vitro. IL-35 increased basal and TNF-α induced pro-angiogenic molecules expression by osteoblasts. Blocking the Th17/IL-17 signalling pathway with plumbagin inhibited the pro-angiogenic effects of IL-35 in osteoblasts. CONCLUSIONS: These results suggested that IL-35 promotes bone formation and angiogenesis by fostering osteoblasts proliferation, inhibiting apoptosis and upregulating pro-angiogenic molecules through Th17/IL-17 related-signalling pathway. Our findings extend the current understanding of mechanisms modulating bone formation and angiogenesis in RA.


Assuntos
Artrite Reumatoide/imunologia , Mediadores da Inflamação/imunologia , Interleucinas , Osteoclastos/fisiologia , Osteogênese , Artrite Reumatoide/patologia , Citocinas/biossíntese , Humanos , Interleucinas/biossíntese , Neovascularização Patológica , Osteoblastos/imunologia , Osteoblastos/patologia , Osteogênese/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia
11.
Front Immunol ; 10: 62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30761134

RESUMO

Type 2 immunity participates in the pathogeneses of helminth infection and allergic diseases. Emerging evidence indicates that the components of type 2 immunity are also involved in maintaining metabolic hemostasis and facilitating the healing process after tissue injury. Numerous preclinical studies have suggested regulation of type 2 immunity-related cytokines, such as interleukin-4, -13, and -33, and cell types, such as M2 macrophages, mast cells, and eosinophils, affects cardiac functions after myocardial infarction (MI), providing new insights into the importance of immune modulation in the infarcted heart. This review provides an overview of the functions of these cytokines and cells in the setting of MI as well as their potential to predict the severity and prognosis of MI.


Assuntos
Imunidade Inata , Infarto do Miocárdio/imunologia , Animais , Polaridade Celular , Colágeno/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Humanos , Inflamação/imunologia , Interleucinas/biossíntese , Macrófagos/imunologia , Mastócitos/imunologia , Camundongos , Infarto do Miocárdio/patologia , Neovascularização Fisiológica/imunologia , Ratos
12.
Int J Mol Sci ; 20(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669479

RESUMO

Trophoblast expressing paternal HLA-C resembles a semiallograft, and could be rejected by maternal T cells. IL-22 seems to be involved in allograft rejection and thus could be responsible for miscarriages. We examined the role of decidual IL-22-producing CD4+ T on human pregnancy. In those experiencing successful pregnancy and those experiencing unexplained recurrent abortion (URA), the levels of IL-22 produced by decidual CD4+ T cells are higher than those of peripheral blood T cells. We found a correlation of IL-22 and IL-4 produced by decidual CD4+ T cells in those experiencing successful pregnancy, not in those experiencing URA. The correlation of IL-22 and IL-4 was also found in the serum of successful pregnancy. A prevalence of CD4+ T cells producing IL-22 and IL-4 (Th17/Th2/IL-22+, Th17/Th0/IL-22+, Th17/Th2/IL-22+, and Th0/IL-22+ cells) was observed in decidua of those experiencing successful pregnancy, whereas Th17/Th1/IL-22+ cells, which do not produce IL-4, are prevalent in those experiencing URA. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells are exclusively present at the embryo implantation site where IL-4, GATA-3, IL-17A, ROR-C, IL-22, and AHR mRNA are expressed. T-bet and IFN-γ mRNA are found away from the implantation site. There is no pathogenic role of IL-22 when IL-4 is also produced by decidual CD4+ cells. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells seem to be crucial for embryo implantation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Decídua/fisiologia , Interleucina-4/biossíntese , Interleucinas/biossíntese , Subpopulações de Linfócitos T/metabolismo , Aborto Habitual/etiologia , Aborto Habitual/metabolismo , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Citocinas/biossíntese , Citocinas/sangue , Feminino , Humanos , Interleucina-4/sangue , Interleucinas/sangue , Modelos Biológicos , Gravidez , Resultado da Gravidez , Gravidez Ectópica/etiologia , Gravidez Ectópica/metabolismo , Subpopulações de Linfócitos T/imunologia
13.
Vet Med Sci ; 5(2): 199-205, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30663866

RESUMO

A pharmacodynamic assay has been previously developed to monitor ciclosporin treatment in dogs by assessing inhibition of cytokine transcription after whole blood stimulation with 12-myristate 13-1 acetate and ionomycin (PMA/I). In this study, whole blood stimulation with either PMA/I or lipopolysaccharide (LPS) was used to assess the effect of multiple drugs (azathioprine, ciclosporin, mycophenolate, leflunomide and prednisone) after a 7-day treatment course on production of cytokines measured with a multiplex assay in healthy dogs (n = 4 for each treatment). Interleukin-10 (IL-10), interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα) were significantly activated by PMA/I stimulation and IL-6, IL-10 and TNFα by LPS stimulation, in the absence of immunosuppressive drugs. After ciclosporin treatment, IL-10, IFNγ and TNFα production was significantly reduced after stimulation with PMA/I compared to pre-treatment. After prednisone treatment, TNFα production was significantly reduced after stimulation with PMA/I or LPS compared to pre-treatment. No significant change was observed after treatment with azathioprine, leflunomide or mycophenolate. This methodology may be useful to monitor dogs not only treated with ciclosporin, but also with prednisone or a combination of both. Further studies are needed to assess the use of this assay in a clinical setting.


Assuntos
Imunossupressores/farmacologia , Interferon gama/biossíntese , Interleucinas/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Animais , Azatioprina/farmacologia , Ciclosporina/farmacologia , Cães , Interferon gama/efeitos dos fármacos , Ionomicina/toxicidade , Leflunomida/farmacologia , Lipopolissacarídeos/toxicidade , Ácido Micofenólico/farmacologia , Prednisona/farmacologia , Acetato de Tetradecanoilforbol/toxicidade , Fator de Necrose Tumoral alfa/efeitos dos fármacos
14.
Ocul Immunol Inflamm ; 27(4): 595-601, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29498905

RESUMO

Purpose: Recent studies have reported that IL-35 has a protective effect in autoimmune disease. In this study, we explored the role of IL-35 in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. Methods: The IL-35/EBI3 and IL-35/P35 mRNA level was assayed by Real-Time PCR. The level of IL-35 in serum was detected by ELISA. PBMCs and monocyte-derived DCs were cultured with or without IL-35 and the concentration of IL-17, IL-10, IFN-γ, IL-6, TNF-α, and IL-1ß in supernatants was tested by ELISA. Results: The serum level of IL-35 is reduced in active VKH patients. The mRNA expression of the two subunits IL-35/EBI3 and IL-35/P35 in PBMCs from patients with active VKH was also decreased. IL-35 significantly inhibited IFN-γ and IL-17 expression and induced IL-10 production by PBMCs and inhibited IL-6 production by monocyte-derived DCs. Conclusion: The current study suggests that a decreased IL-35 expression may be involved in the pathogenesis of VKH disease.


Assuntos
Regulação da Expressão Gênica , Interleucinas/genética , RNA/genética , Uveíte/genética , Síndrome Uveomeningoencefálica/complicações , Adulto , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Interleucinas/biossíntese , Masculino , Estudos Retrospectivos , Uveíte/etiologia , Uveíte/metabolismo , Síndrome Uveomeningoencefálica/diagnóstico , Síndrome Uveomeningoencefálica/genética
15.
J Allergy Clin Immunol ; 143(1): 142-154, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30121291

RESUMO

BACKGROUND: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. OBJECTIVE: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. METHODS: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. RESULTS: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10-5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10-19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22-high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. CONCLUSIONS: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucinas/biossíntese , Pele/metabolismo , Adulto , Anticorpos Monoclonais Humanizados , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Pele/imunologia , Pele/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia
16.
J Microbiol Biotechnol ; 29(2): 304-310, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30544288

RESUMO

Interleukin-21 is a common γ-chain cytokine that controls the immune responses of B cells, T cells, and natural killer cells. Targeting IL-21 to strengthen the immune system is promising for the development of vaccines as well as anti-infection and anti-tumor therapies. However, the practical application of IL-21 is limited by the high production cost. In this study, we improved IL-21 production by codon optimization and selection of appropriate signal peptide in CHO-K1 cells. Codon-optimized or non-optimized human IL-21 was stably transfected into CHO-K1 cells. IL-21 expression was 10-fold higher for codon-optimized than non-optimized IL-21. We fused five different signal peptides to codon-optimized mature IL-21 and evaluated their effect on IL-21 production. The best result (a 3-fold increase) was obtained using a signal peptide derived from human azurocidin. Furthermore, codon-optimized IL-21 containing the azurocidin signal peptide promoted IFN-γ secretion and STAT3 phosphorylation in NK-92 cells similar to codon-optimized IL-21 containing original signal peptide. Collectively, these results indicate that codon optimization and azurocidin signal peptides provide an efficient approach for the high-level production of IL-21 as a biopharmaceutical.


Assuntos
Códon/genética , Interleucinas/biossíntese , Interleucinas/genética , Sinais Direcionadores de Proteínas/genética , Animais , Medicamentos Biossimilares , Células CHO , Cricetulus , Vetores Genéticos , Humanos , Interferon gama/metabolismo , Interleucinas/metabolismo , Fosforilação , Engenharia de Proteínas , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Fator de Transcrição STAT3/metabolismo , Transfecção
17.
Biomed Pharmacother ; 110: 727-732, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30554110

RESUMO

Cigarette smoke (CS) is a very important cause of pulmonary inflammatory diseases. Interleukin (IL)-35 is a novel anti-inflammatory cytokine but its role in CS-mediated lung inflammation remains unclear. In the present study, we examined the effect of IL-35 expression on CS-induced lung inflammation in mice. A plasmid DNA expressing IL-35 was injected into mice via a hydrodynamic-based gene delivery that were subsequently exposed to CS three times a day for 5 days. We found that IL-35 expression inhibited pulmonary inflammatory infiltration, lung tissue lesions, mucus secretion, and myeloperoxidase activity in CS-treated mice. Moreover, IL-35 expression decreased the production of IL-1ß, tumor necrosis factor-α, IL-6, and IL-17, but increased the level of IL-10 in bronchoalveolar lavage fluids and lung tissues from CS-challenged mice. These results suggest that in vivo expression of IL-35 can protect against CS-induced lung inflammation and may be a therapeutic target in CS-related pulmonary diseases.


Assuntos
Fumar Cigarros/efeitos adversos , Interleucinas/biossíntese , Pneumonia/metabolismo , Pneumonia/prevenção & controle , Fumaça/efeitos adversos , Animais , Expressão Gênica , Exposição por Inalação/efeitos adversos , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente
18.
J Biol Chem ; 294(7): 2386-2396, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30573681

RESUMO

Interleukin 34 (IL-34) constitutes a cytokine that shares a common receptor, colony-stimulating factor-1 receptor (CSF-1R), with CSF-1. We recently identified a novel type of monocytic cell termed follicular dendritic cell-induced monocytic cells (FDMCs), whose differentiation depended on CSF-1R signaling through the IL-34 produced from a follicular dendritic cell line, FL-Y. Here, we report the functional mechanisms of the IL-34-mediated CSF-1R signaling underlying FDMC differentiation. CRIPSR/Cas9-mediated knockout of the Il34 gene confirmed that the ability of FL-Y cells to induce FDMCs completely depends on the IL-34 expressed by FL-Y cells. Transwell culture experiments revealed that FDMC differentiation requires a signal from a membrane-anchored form of IL-34 on the FL-Y cell surface, but not from a secreted form, in a direct interaction between FDMC precursor cells and FL-Y cells. Furthermore, flow cytometric analysis using an anti-IL-34 antibody indicated that IL-34 was also expressed on the FL-Y cell surface. Thus, we explored proteins interacting with IL-34 in FL-Y cells. Mass spectrometry analysis and pulldown assay identified that IL-34 was associated with the molecular chaperone 78-kDa glucose-regulated protein (GRP78) in the plasma membrane fraction of FL-Y cells. Consistent with this finding, GRP78-heterozygous FL-Y cells expressed a lower level of IL-34 protein on their cell surface and exhibited a reduced competency to induce FDMC differentiation compared with the original FL-Y cells. These results indicated a novel GRP78-dependent localization and specific function of IL-34 in FL-Y cells related to monocytic cell differentiation.


Assuntos
Diferenciação Celular/fisiologia , Membrana Celular/metabolismo , Células Dendríticas Foliculares/metabolismo , Regulação da Expressão Gênica/fisiologia , Proteínas de Choque Térmico/metabolismo , Interleucinas/biossíntese , Monócitos/metabolismo , Animais , Linhagem Celular , Membrana Celular/genética , Células Dendríticas Foliculares/citologia , Proteínas de Choque Térmico/genética , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/citologia
19.
Toxicology ; 411: 93-100, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445053

RESUMO

Recent studies have shown that the estrogen receptor α (ERα), but not ERß, is involved in the proinflammatory and propruritic responses in cutaneous allergy. In addition, results from our recent study showed that while oral administration of the rather ERß-selective agonist bisphenol A exacerbated the respiratory allergic inflammation, the potential inflammatory reaction in the skin was decreased after administration of bisphenol A. This study aimed to elucidate whether ERα and ERß are involved in the progression of an allergic airway inflammation. We performed an in vivo experiment using an animal model of allergic airway inflammation using male BALB/c mice to confirm an increase in the proinflammatory response induced by propylpyrazoletriol (PPT), an ERα agonist, and diarylpropionitrile (DPN), an ERß agonist. Oral administration of PPT or DPN showed a significant increase in the inflammation of the lung and infiltration of eosinophils. While the expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to PPT or DPN, administration of these agonists significantly increased the expression of IL-33. The mechanism underlying the development of such allergic inflammatory responses was determined by an in vitro study using the human bronchial epithelial cell line (BEAS-2B) and the human eosinophilic leukemia cell line (EoL-1). Activated cells were exposed to PPT or DPN for 24 h, and the cytokine levels were measured. The IL-33 levels in BEAS-2B cells increased significantly after exposure to PPT or DPN. In addition, pretreatment with PPT or DPN increased the expression of IL-8 in activated EoL-1 cells. Our findings indicate that ERα and ERß are involved in the proinflammatory response in respiratory allergy, and their effects may be mediated by an increase in the expression of IL-33 and infiltration of eosinophils.


Assuntos
Eosinófilos/patologia , Receptor alfa de Estrogênio/biossíntese , Receptor beta de Estrogênio/biossíntese , Interleucina-33/genética , Hipersensibilidade Respiratória/patologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Linhagem Celular , Receptor alfa de Estrogênio/agonistas , Receptor beta de Estrogênio/agonistas , Humanos , Inflamação/patologia , Interleucinas/biossíntese , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nitrilos/toxicidade , Fenóis/toxicidade , Propionatos/toxicidade , Pirazóis/toxicidade
20.
Biomed Pharmacother ; 110: 692-699, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30553196

RESUMO

Glycyrrhizin, a triterpenoid compound, has been reported to be an anti-inflammatory agent for the treatment of a variety of inflammatory diseases including hepatitis. However, the mechanism by which glycyrrhizin inhibits inflammation is unclear. Using a Con A-induced hepatitis model in mice, we found that administration of glycyrrhizin ameliorates Con A-induced liver injury, which manifests as reduction in the production of inflammatory cytokines IFN-γ, IL-6 and IL-17, as well as serum alanine aminotransferase (ALT). Blockade of IL-17 dramatically mitigates liver injury resulting from Con A challenge. Interestingly, at both the mRNA and protein levels, the endogenous alarmin inflammatory molecule high-mobility group box 1 (HMGB1) is significantly decreased in mice injected with glycyrrhizin combined with Con A compared to those injected with Con A alone. In contrast, the administration of glycyrrhizin with Con A challenge up-regulates the production of IL-25. Furthermore, an increase in the proportion of protective lymphocyte subset, Gr-1+ CD11b+ (Myeloid-Derived Suppressor Cell, MDSCs), could be induced by increased IL-25 to restrain immune cell activation and favor the resolution of detrimental immune reactions caused by Con A challenge. The results indicate that glycyrrhizin plays a protective role in Con A-induced hepatitis. This protective role is particularly associated with reducing the production of IL-17 and enhancing the expression of IL-25. The present study may provide a new strategy for the treatment of acute hepatitis in the clinical setting.


Assuntos
Concanavalina A/toxicidade , Ácido Glicirrízico/uso terapêutico , Hepatite/tratamento farmacológico , Hepatite/metabolismo , Interleucina-17/biossíntese , Interleucinas/biossíntese , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ácido Glicirrízico/farmacologia , Interleucina-17/antagonistas & inibidores , Interleucinas/agonistas , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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