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1.
Int J Mol Sci ; 24(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36674744

RESUMO

The epithelium-derived cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are important mediators that initiate innate type 2 immune responses in asthma. Leukotriene receptor antagonists (LTRAs) are commonly used to prevent asthma exacerbations. However, the effects of LTRAs on epithelium-derived cytokines expression in airway epithelial cells are unclear. This study aimed to investigate the effects of LTRAs on the expression of epithelium-derived cytokines in human airway epithelial cells and to explore possible underlying intracellular processes, including epigenetic regulation. A549 or HBE cells in air-liquid interface conditions were pretreated with different concentrations of LTRAs. The expression of epithelium-derived cytokines and intracellular signaling were investigated by real-time PCR, enzyme-linked immunosorbent assay, and Western blot. In addition, epigenetic regulation was investigated using chromatin immunoprecipitation analysis. The expression of IL-25, IL-33, and TSLP was increased under LTRAs treatment and suppressed by inhaled corticosteroid cotreatment. Montelukast-induced IL-25, IL-33, and TSLP expression were mediated by the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways and regulated by histone H3 acetylation and H3K36 and H3K79 trimethylation. LTRAs alone might increase inflammation and exacerbate asthma by inducing the production of IL-25, IL-33, and TSLP; therefore, LTRA monotherapy may not be an appropriate therapeutic option for asthma.


Assuntos
Asma , Humanos , Interleucina-33/metabolismo , Epigênese Genética , Citocinas/metabolismo , Células Epiteliais/metabolismo , Asma/tratamento farmacológico , Asma/genética
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 39(1): 9-14, 2023 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-36631009

RESUMO

Objective To investigate how vitamin D (VD) affects fine particulate matter (PM2.5)-induced autophagy and cytokines production in A549 human alveolar epithelial cells. Methods PM2.5 samples were prepared at the upper part of an acetylene diffusion flame burner. A549 cells were treated with PM2.5 in vitro, and/or were treated with VD or autophagy inhibitor 3-methyladenine (3-MA). Western blot analysis was employed to analyze the level of LC3-II/I and Beclin-1 in A549 cells with different groups. Real time quantitative PCR was used to detect the mRNA expression of interleukin-25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP). The formation of autophagosomes was observed by transmission electron microscopy. Results LC3-II/I ratio and beclin-1 protein expression were found increased in A549 cells after PM2.5 treatment, and autophagosome were increased too. There was a marked decrease of PM2.5-induced autophagy with VD treatment. After 3-MA treatment, the autophagy was inhibited. Then, PM2.5 continued to induce autophagy, while VD could also reverse it. PM2.5 promoted the secretion of IL-25, IL-33 and TSLP by inducing autophagy in A549 cells while this process was inhibited by 3-MA and VD. Conclusion VD can inhibit PM2.5-induced autophagy and cytokine release in A549 cells, thus playing a protective role.


Assuntos
Células Epiteliais Alveolares , Citocinas , Humanos , Células Epiteliais Alveolares/metabolismo , Citocinas/metabolismo , Interleucina-33/metabolismo , Vitamina D/metabolismo , Autofagia , Material Particulado/efeitos adversos , Proteína Beclina-1/metabolismo , Células A549 , Células Epiteliais/metabolismo
3.
J Exp Med ; 220(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36520518

RESUMO

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.


Assuntos
Interleucina-33 , Microglia , Animais , Camundongos , Microglia/metabolismo , Interleucina-33/metabolismo , Sinapses/metabolismo , Encéfalo/metabolismo , Convulsões/metabolismo , Camundongos Endogâmicos C57BL
4.
Cell Signal ; 102: 110552, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36481410

RESUMO

It is well known that the T Helper (Th)2 bias plays a critical role in allergic asthma. Whereas the Th2 bias is maintained in the local tissues is uncertain. IL-33 is vital for the development of the Th2 polarization. TWIST-1 has an effect on regulating cellular functions. The aberrant activation of RAS sustains certain cellular activities. The aim of this study is to study the role of the interaction between activation of TWIST1 and RAS in inducing and maintaining Th2 polarization in allergic asthma. The epithelial cells of the airways (AEC) were isolated from the broncho-alveolar lavage fluids in patients with asthma. The mediators involved in the over-expression of IL-33 were determined by RNA sequencing. A mouse model was established to test the role of TWIST1 and RAS in developing allergic asthma. We observed a strong expression of TWIST1 in patients with allergic asthma that showed a positive correlation with asthmatic responses. TWIST1 favored the expression of the IL-33 in the AEC. Twist1-deficient AEC-carrying mice did not induce Th2 polarization in the airways. The expression TWIST1 in AECs was positively associated with RAS activation in AECs in patients with allergic asthma. The interaction between RAS and TWIST1 in AECs sustained airway allergic inflammation. Inhibition of TWIST1 or RAS prevented asthma-like inflammation in the mouse airways. In summary, the interaction between TWIST1 and RAS induces and maintains IL-33 expression in AECs to facilitate allergic inflammation in the respiratory tract. Inhibition of TWIST1 or RAS can prevent experimental allergic asthma.


Assuntos
Asma , Interleucina-33 , Animais , Camundongos , Asma/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Inflamação/metabolismo , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Células Th2/metabolismo
5.
J Cell Mol Med ; 27(2): 304-308, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36573439

RESUMO

Evidence points to the indispensable function of alveolar macrophages (AMs) in normal lung development and tissue homeostasis. However, the importance of AMs in bronchopulmonary dysplasia (BPD) has not been elucidated. Here, we identified a significant role of abnormal AM proliferation and polarization in alveolar dysplasia during BPD, which is closely related to the activation of the IL-33-ST2 pathway. Compared with the control BPD group, AMs depletion partially abolished the epithelialmesenchymal transition process of AECII and alleviated pulmonary differentiation arrest. In addition, IL-33 or ST2 knockdown has protective effects against lung injury after hyperoxia, which is associated with reduced AM polarization and proliferation. The protective effect disappeared following reconstitution of AMs in injured IL-33 knockdown mice, and the differentiation of lung epithelium was blocked again. In conclusion, the IL-33-ST2 pathway regulates AECII transdifferentiation by targeting AMs proliferation and polarization in BPD, which shows a novel strategy for manipulating the IL-33-ST2-AMs axis for the diagnosis and intervention of BPD.


Assuntos
Displasia Broncopulmonar , Hiperóxia , Humanos , Recém-Nascido , Animais , Camundongos , Displasia Broncopulmonar/complicações , Macrófagos Alveolares/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Transdiferenciação Celular , Interleucina-33/genética , Interleucina-33/metabolismo , Pulmão/metabolismo , Modelos Animais de Doenças , Animais Recém-Nascidos
6.
J Ethnopharmacol ; 303: 116047, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36528211

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Bronchial asthma, a non-communicable chronic respiratory disease, affects people of all ages. An important pathological feature of bronchial asthma is airway remodeling. Hyssopus cuspidatus Boriss. has been used to treat bronchial asthma for over 100 years in Uygur medicine. The ethanol extract of Hyssopus cuspidatus Boriss.(JAX2) can improve airway inflammation in asthma. However, the anti-asthmatic airway-remodeling effect of JAX2 is unclear. AIM OF THE STUDY: The current study investigated the anti-airway remodeling effect of JAX2 and elucidated its mechanism of action. MATERIALS AND METHODS: The present study established an ovalbumin-induced mouse model of asthma and platelet-derived growth factor-BB-induced human airway smooth muscle cells (hASMCs) proliferation model, with dexamethasone (DEX) and feining tablets (FNP) designated as positive control drugs. Pathological changes in lung tissues were observed using hematoxylin and eosin staining. Interleukin (IL)-5, IL-10, IL-13, and IL-33 levels in the bronchoalveolar lavage fluid (BALF) and serum of mice were determined using enzyme-linked immunosorbent assay (ELISA). Changes in the expression and distribution of TGF-ß1, p-ERK1/2, Smad2/3, and p-Smad3 in lung tissues were determined using immunohistochemistry. Western blotting (WB) was used to determine the protein levels of p-ERK1/2 in lung tissues and cells. MTS assay was used to determine the effects of JAX2 on cell proliferation. IL-5, IL-10, IL-13, MMP-2, and MMP-9 levels in the cell supernatant were determined using ELISA. HASMCs migration was observed using the scratch and transwell methods. The effect of JAX2 on the hASMCs cycle was determined using flow cytometry. RESULTS: JAX2 significantly improved the pathological status of lung tissues in asthmatic mice. It could also significantly reduce IL-5, IL-13, and IL-33 levels in the BALF and serum of asthmatic mice in a dose-dependent manner and significantly increase IL-10 levels. TGF-ß1, p-ERK1/2, Smad2/3, and p-Smad3 expression in lung tissues were decreased in a dose-dependent manner. The protein level of p-ERK1/2 in lung tissues was also reduced. JAX2 could significantly inhibit the proliferation and migration of PDGF-BB-induced hASMCs. IL-5, IL-13, MMP-9, and MMP-2 levels decreased significantly, and IL-10 levels increased significantly in a dose-dependent manner in the cell supernatant. JAX2 could block hASMCs in the G0/G1 phase, thereby inhibiting cell proliferation. p-ERK1/2 protein levels were found to decrease in a dose-dependent manner. CONCLUSIONS: JAX2 significantly inhibits airway remodeling in asthma. Its mechanism of action may be inhibiting the proliferation and migration of hASMCs, releasing inflammatory factors and metalloproteinases, activating the ERK1/2 signal pathway, and promoting the secretion of anti-inflammatory factors.


Assuntos
Asma , Hyssopus , Extratos Vegetais , Animais , Humanos , Camundongos , Asma/patologia , Líquido da Lavagem Broncoalveolar , Proliferação de Células , Modelos Animais de Doenças , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Interleucina-5/metabolismo , Pulmão , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Ovalbumina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Hyssopus/química , Extratos Vegetais/farmacologia
7.
Ecotoxicol Environ Saf ; 249: 114381, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36508801

RESUMO

Black carbon (BC) is an important component of atmospheric PM 2.5 and the second largest contributor to global warming. 1,4-naphthoquinone-coated BC (1,4 NQ-BC) is a secondary particle with great research value, so we chose 1,4 NQ-BC as the research object. In our study, mitochondria and lysosomes were selected as targets to confirm whether they were impaired by 1,4 NQ-BC, label free proteomics technology, fluorescent probes, qRT-PCR and western blots were used to investigate the mechanism of 1,4 NQ-BC toxicity. We found 494 differentially expressed proteins (DEPs) in mitochondria and 86 DEPs in lysosomes using a proteomics analysis of THP1 cells after 1,4 NQ-BC exposure for 24 h. Through proteomics analysis and related experiments, we found that 1,4 NQ-BC can damage THP-1-M cells by obstructing autophagy, increasing lysosomal membrane permeability, disturbing the balance of ROS, and reducing the mitochondrial membrane potential. It is worth noting that 1,4 NQ-BC prevented the removal of FTL by inhibiting autophagy, and increased IL-33 level by POR/FTL/IL-33 axis. We first applied proteomics to study the damage mechanism of 1,4 NQ-BC on THP1 cells. Our research will enrich knowledge of the mechanism by which 1,4 NQ-BC damages human macrophages and identify important therapeutic targets and adverse outcome pathways for 1,4 NQ-BC-induced damage.


Assuntos
Interleucina-33 , Naftoquinonas , Humanos , Interleucina-33/metabolismo , Regulação para Cima , Naftoquinonas/metabolismo , Carbono/metabolismo , Apoferritinas/metabolismo
8.
Nature ; 611(7936): 578-584, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323778

RESUMO

Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites<sup>1,2</sup>, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.


Assuntos
Ácidos e Sais Biliares , Fibras na Dieta , Microbioma Gastrointestinal , Inflamação , Inulina , Animais , Humanos , Camundongos , Ácidos e Sais Biliares/metabolismo , Ácido Cólico/farmacologia , Fibras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Imunidade Inata , Inflamação/induzido quimicamente , Inflamação/classificação , Inflamação/patologia , Inulina/farmacologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Metabolômica , Pulmão/efeitos dos fármacos , Pulmão/patologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/patologia , Interleucina-33/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia
9.
BMC Immunol ; 23(1): 52, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316644

RESUMO

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are the most dominant ILCs in heart tissue, and sex-related differences exist in mouse lung ILC2 phenotypes and functions; however, it is still unclear whether there are sex differences in heart ILC2s. RESULTS: Compared with age-matched wild-type (WT) male mice, 8-week-old but not 3-week-old WT female mice harbored an obviously greater percentage and number of heart ILC2s in homeostasis. However, the percentage of killer-cell lectin-like receptor G1 (Klrg1)- ILC2s was higher, but the Klrg1+ ILC2s were lower in female mice than in male mice in both heart tissues of 3- and 8-week-old mice. Eight-week-old Rag2-/- mice also showed sex differences similar to those of age-matched WT mice. Regarding surface marker expression, compared to age-matched male mice, WT female mice showed higher expression of CD90.2 and Ki67 and lower expression of Klrg1 and Sca-1 in heart total ILC2s. There was no sex difference in IL-4 and IL-5 secretion by male and female mouse heart ILC2s. Increased IL-33 mRNA levels within the heart tissues were also found in female mice compared with male mice. By reanalyzing published single-cell RNA sequencing data, we found 2 differentially expressed genes between female and male mouse heart ILC2s. Gene set variation analysis revealed that the glycine, serine and threonine metabolism pathway was upregulated in female heart ILC2s. Subcluster analysis revealed that one cluster of heart ILC2s with relatively lower expression of Semaphorin 4a and thioredoxin interacting protein but higher expression of hypoxia-inducible lipid droplet-associated. CONCLUSIONS: These results revealed greater numbers of ILC2s, higher expression of CD90.2, reduced Klrg1 and Sca-1 expression in the hearts of female mice than in male mice and no sex difference in IL-4 and IL-5 production in male and female mouse heart ILC2s. These sex differences in heart ILC2s might be due to the heterogeneity of IL-33 within the heart tissue.


Assuntos
Coração , Imunidade Inata , Interleucina-33 , Linfócitos , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Interleucina-33/genética , Interleucina-33/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Pulmão/metabolismo , Linfócitos/metabolismo , Camundongos Knockout , Antígenos Thy-1/metabolismo
10.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362030

RESUMO

Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory-immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.


Assuntos
Gengivite , Interleucina-33 , Mastócitos , Humanos , Citocinas , Gengivite/metabolismo , Gengivite/patologia , Inflamação , Interleucina-33/metabolismo , Mastócitos/metabolismo , Mastócitos/patologia , Periodontite/metabolismo , Periodontite/patologia , Interleucina-1/metabolismo
11.
Int J Mol Sci ; 23(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36362246

RESUMO

Interleukin-33 (IL-33) is an immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. IL-33 is abundant within the brain and spinal cord tissues where it acts as a key cytokine to coordinate the exchange between the immune and central nervous system (CNS). In this review, we report the recent advances to our knowledge regarding the role of IL-33 and of its receptor ST2 in cerebral malaria, and in particular, we highlight the pivotal role that IL-33/ST2 signaling pathway could play in brain and cerebrospinal barriers permeability. IL-33 serum levels are significantly higher in children with severe Plasmodium falciparum malaria than children without complications or noninfected children. IL-33 levels are correlated with parasite load and strongly decrease with parasite clearance. We postulate that sequestration of infected erythrocytes or merozoites liberation from schizonts could amplify IL-33 production in endothelial cells, contributing either to malaria pathogenesis or recovery.


Assuntos
Malária Cerebral , Malária Falciparum , Criança , Humanos , Interleucina-33/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Células Endoteliais/metabolismo , Malária Falciparum/parasitologia , Citocinas , Plasmodium falciparum/metabolismo
12.
Parasit Vectors ; 15(1): 386, 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36271450

RESUMO

BACKGROUND: Clonorchiasis caused by Clonorchis sinensis is a zoonotic parasitic disease characterized by cholangitis, biliary proliferation, biliary fibrosis, and even cholangiocarcinoma. Our previous study showed that the expression of interleukin (IL)-33 is increased in both humans and mice infected by C. sinensis, suggesting that IL-33 is potentially involved in the pathogenesis of clonorchiasis. However, the roles and potential mechanism of IL-33 underlying remain unknown. METHODS: Wild-type (WT) and IL-33 knockout (KO) mice (BALB/c female mice) were orally infected with 45 metacercariae of C. sinensis for 8 weeks. Biliary injuries and fibrosis were extensively evaluated. Hepatic type II cytokines (IL-4, IL-13, and IL-10) were detected by ELISA. RESULTS: For wild-type mice, we found that the mice infected with C. sinensis showed severe biliary injuries and fibrosis compared with the normal mice that were free from worm infection. In addition, the levels of type II cytokines such as IL-4, IL-13, and IL-10 in infected wild-type mice were significantly higher than in the control mice without infection (P < 0.05). However, IL-33 deficiency (IL-33 KO) prevents the augmentation of biliary injuries and fibrosis caused by C. sinensis infection. Furthermore, the increased levels of these type II cytokines induced by worm infection were also reversed in IL-33 KO mice. CONCLUSION: Our present study demonstrates that IL-33 contributes to the pathogenesis of C. sinensis-induced biliary injuries and repair, which can potentially orchestrate type 2 responses. These findings highlight the pathophysiological role of IL-33 in the progression of clonorchiasis.


Assuntos
Clonorquíase , Clonorchis sinensis , Interleucina-13 , Animais , Feminino , Humanos , Camundongos , Clonorquíase/imunologia , Clonorchis sinensis/fisiologia , Citocinas/metabolismo , Fibrose , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Interleucina-4/genética , Camundongos Endogâmicos BALB C
13.
Acta Neurobiol Exp (Wars) ; 82(3): 273-283, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36214710

RESUMO

Multiple sclerosis (MS) is the most typical chronic inflammatory, autoimmune demyelinating disease of the central nervous system (CNS) which leads to physical dysfunction and paralysis in patients. A commonly used animal model for this disease is experimental autoimmune encephalomyelitis (EAE). Daphnetin (7,8­dihydroxycoumarin) has been reported to exert various pharmacological activities, such as being neuroprotective and anti­inflammatory, together with having antioxidant, anticancer, and antiviral properties. Eight­week­old C57BL/6 female mice were segregated into 3 groups, namely 1) a control group receiving PBS, 2) a low­dose treatment group receiving 2 mg/kg of daphnetin, and, 3) a high­dose treatment group receiving 8 mg/kg of daphnetin. EAE was induced with a subcutaneous injection of a combination of myelin oligodendrocyte glycoprotein (MOG) and complete Freund's adjuvant. On the day of induction, and again two days later, mice were injected intraperitoneally with pertussis toxin. Histological studies showed low lymphocyte infiltration and demyelination in the high and low dose treated groups. The ratio of spleen Treg cells and the levels of IL­4, IL­10, TGF­ß, and IL­33 enhanced significantly in the treatment group related to the control group. Furthermore, both IL­27 and IL­35 were also enhanced significantly in the treatment group compared to the control group. Moreover, the levels of IFN­Î³, TNF­α, and IL­17 displayed a noticeable reduction in the daphnetin treated group. Daphnetin appears to improve the disease by increasing the expression of anti­inflammatory cytokines and transcription factors (IL­4, IL­10, IL­33, GATA3, TGF­ß, FoxP3), and reducing the production of pro­inflammatory cytokines and transcription factors (IFN­Î³, STAT4, T­bet, IL­17, STAT3, ROR­Î³t, TNF­α).


Assuntos
Encefalomielite Autoimune Experimental , Umbeliferonas , Animais , Anti-Inflamatórios , Antioxidantes/metabolismo , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Adjuvante de Freund , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-27/metabolismo , Interleucina-33/metabolismo , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Toxina Pertussis , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Células Th17/metabolismo , Células Th17/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Umbeliferonas/farmacologia
14.
Cells ; 11(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36291105

RESUMO

Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an "alarmin" by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.


Assuntos
Doenças Autoimunes , Infecções , Inflamação , Interleucina-1 , Interleucina-33 , Neoplasias , Humanos , Doenças Autoimunes/imunologia , Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Neoplasias/imunologia , Microambiente Tumoral , Inflamação/imunologia , Transplante de Órgãos , Infecções/imunologia
15.
Int J Mol Sci ; 23(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36293218

RESUMO

Clostridioides difficile (C. difficile), is a major cause of nosocomial diarrhea and colitis. C. difficile flagellin FliC contributes toxins to gut inflammation by interacting with the immune Toll-like receptor 5 (TLR5) to activate nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways. Flagella of intracellular pathogens can activate the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome pathway. In this study, we assessed whether flagellin of the extracellular bacterium C. difficile internalizes into epithelial cells and activates the NLRC4 inflammasome. Confocal microscopy showed internalization of recombinant green fluorescent protein (GFP)-FliC into intestinal Caco-2/TC7 cell line. Full-length GFP-FliC activates NLRC4 in Caco-2/TC7 cells in contrast to truncated GFP-FliC lacking the C-terminal region recognized by the inflammasome. FliC induced cleavage of pro-caspase-1 into two subunits, p20 and p10 as well as gasdermin D (GSDMD), suggesting the caspase-1 and NLRC4 inflammasome activation. In addition, colocalization of GFP-FliC and pro-caspase-1 was observed, indicating the FliC-dependent NLRC4 inflammasome activation. Overexpression of the inflammasome-related interleukin (interleukin (IL)-1ß, IL-18, and IL-33) encoding genes as well as increasing of the IL-18 synthesis was detected after cell stimulation. Inhibition of I-kappa-B kinase alpha (IKK-α) decreased the FliC-dependent inflammasome interleukin gene expression suggesting a role of the NF-κB pathway in regulating inflammasome. Altogether, these results suggest that FliC internalizes into the Caco-2/TC7 cells and activates the intracellular NLRC4 inflammasome thus contributing to the inflammatory process of C. difficile infection.


Assuntos
Clostridioides difficile , Receptor 5 Toll-Like , Humanos , Receptor 5 Toll-Like/metabolismo , Inflamassomos/metabolismo , Flagelina/genética , NF-kappa B/metabolismo , Caspase 1/metabolismo , Interleucina-18/metabolismo , Interleucina-33/metabolismo , Clostridioides , Células CACO-2 , Proteínas de Fluorescência Verde/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo
16.
J Immunol ; 209(8): 1595-1605, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36165171

RESUMO

Regulatory T cells (Tregs) that express the transcription factor Foxp3 have a critical role in limiting inflammatory processes and tissue damage. Whether Tregs are functional in maintaining epithelial barriers and in control of tight junction expression has not yet been explored. In this study, we investigated the effect of Treg deficiency on the airway epithelial barrier in an experimental murine model in which diphtheria toxin was repeatedly injected in Foxp3-diphtheria toxin receptor (DTR) mice to deplete Tregs. This resulted in spontaneous peribronchial inflammation and led to a systemic and local increase of IL-4, IL-5, CCL3, IFN-γ, and IL-10 and a local (lung) increase of IL-6 and IL-33 and decreased amphiregulin levels. Moreover, Treg depletion increased airway permeability and decreased epithelial tight junction (protein and mRNA) expression. CTLA4-Ig treatment of Treg-depleted mice almost completely prevented barrier dysfunction together with suppression of lung inflammation and cytokine secretion. Treatment with anti-IL-4 partly reversed the effects of Treg depletion on tight junction expression, whereas neutralization of IL-6 of IFN-γ had either no effect or only a limited effect. We conclude that Tregs are essential to protect the epithelial barrier at the level of tight junctions by restricting spontaneous T cell activation and uncontrolled secretion of cytokines, in particular IL-4, in the bronchi.


Assuntos
Toxina Diftérica , Linfócitos T Reguladores , Abatacepte/farmacologia , Anfirregulina/metabolismo , Animais , Citocinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-33/metabolismo , Interleucina-5/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Mucosa Respiratória/metabolismo , Linfócitos T Reguladores/metabolismo
17.
Int J Mol Sci ; 23(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36142703

RESUMO

Bisphenol S (BPS) is increasingly being used as an alternative for bisphenol A; however, its health effects remain unclear. We investigated the effects of oral exposure to low-dose BPS on allergic asthma. C3H/HeJ male mice were intratracheally administered with allergen (ovalbumin (OVA), 1 µg/animal) every 2 weeks from 6 to 11 weeks old. BPS was ingested by drinking water at doses equivalent to 0.04, 0.4, and 4 µg/kg/day. We then examined pulmonary inflammation, airway hyperresponsiveness, serum OVA-specific immunoglobulin (Ig) levels, Th2 cytokine/chemokine production, and mediastinal lymph node (MLN) cell activities. Compared with OVA alone, moderate-dose BPS (BPS-M) with OVA significantly enhanced pulmonary inflammation, airway hyperresponsiveness, and OVA-specific IgE and IgG1. Furthermore, interleukin (IL)-5, IL-13, IL-33, and CCL11/Eotaxin protein levels in the lungs increased. Conversely, these allergic responses were reduced in the high-dose BPS+OVA group. In MLN cells, BPS-M with OVA increased the total cell count and activated antigen-presenting cells including conventional dendritic cell subset (cDC2). After OVA restimulation, cell proliferation and Th2 cytokine production (IL-4, IL-5, and IL-13) in the culture supernatant also increased. Therefore, oral exposure to low-dose BPS may exacerbate allergic asthmatic responses by enhancing Th2-polarized responses and activating the MLN cells.


Assuntos
Asma , Água Potável , Pneumonia , Hipersensibilidade Respiratória , Alérgenos/metabolismo , Animais , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E , Imunoglobulina G/metabolismo , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Interleucina-4/metabolismo , Interleucina-5 , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Ovalbumina/metabolismo , Fenóis , Pneumonia/metabolismo , Hipersensibilidade Respiratória/metabolismo , Sulfonas , Células Th2
18.
Int J Mol Sci ; 23(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36142776

RESUMO

Mast cells (MC) are a key effector cell in multiple types of immune responses, including atopic conditions. Allergic diseases have been steadily rising across the globe, creating a growing public health problem. IgE-mediated activation of MCs leads to the release of potent mediators that can have dire clinical consequences. Current therapeutic options to inhibit MC activation and degranulation are limited; thus, a better understanding of the mechanisms that regulate MC effector functions in allergic inflammation are necessary in order to develop effective treatment options with minimal side effects. Several cytokines have been identified that play multifaceted roles in regulating MC activation, including TGFß, IL-10, and IL-33, and others that appear to serve primarily anti-inflammatory functions, including IL-35 and IL-37. Here, we review the literature examining cytokines that regulate MC-mediated allergic immune responses.


Assuntos
Citocinas , Mastócitos , Degranulação Celular , Citocinas/metabolismo , Humanos , Imunoglobulina E , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-33/metabolismo , Mastócitos/metabolismo , Fator de Crescimento Transformador beta/metabolismo
19.
Clin Respir J ; 16(11): 696-707, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36082495

RESUMO

OBJECTIVES: Interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are the important drivers for excessive type-2 immunity. It has been well elucidated that IL-25/IL-33/TSLP plays an important role in allergic airway inflammation and remodeling, whereas their roles in idiopathic pulmonary fibrosis (IPF) still remained largely unclear. Herein, the aim of the review is to discuss the potential role and mechanism of IL-25/IL-33/TSLP on IPF by literature analysis and summary. DATA SOURCE: We have done a literature search using the following terms: ("idiopathic pulmonary fibrosis" OR "IPF" OR "lung fibrosis") and (TSLP or "thymic stromal lymphopoietin" or IL-25 OR IL-17E OR IL-33) from the database of PubMed published in English up to July 2018. STUDY SELECTION: We have totally found 58 articles by using the retrieval terms mentioned above. By careful title and abstract reading, 10 original research articles of high quality were enrolled for the full text reading and analysis. Two additional relevant studies were also included during the course of literature readings. RESULTS: IL-25/IL-33/TSLP and their corresponding receptors, that is, IL-17BR/ST2L/TSLPR, are shown to be up-regulated both in IPF patients and bleomycin (BLM)-induced lung fibrosis mice model. IL-25 may promote lung fibrosis by activating IL-17BR+fibroblast and IL-17BR+ILC2 (type 2 innate lymphoid cell). Full length (fl)-IL-33, as a transcription factor mainly in the cell nucleus, mediated non-atopic lung inflammation and fibrosis by modulating expressions of several pro-fibrotic mediators, including transforming growth factor (TGF)-b1. By contrast, mature (m)-IL-33 potentiates lung fibrosis by recruiting ST2L+M2 macrophages and ST2L+ILC2 to enlarge type 2 immunity. TSLP was shown to directly promote CCL2 expression in primary human lung fibroblasts (pHLFs). CONCLUSION: IL-25/IL-33/TSLP contributes to non-allergic lung fibrosis by mediating persistent abnormal epithelial-mesenchymal crosstalk. IL-25/IL-33/TSLP may serve the promising novel target for the treatment of IPF.


Assuntos
Citocinas , Fibrose Pulmonar Idiopática , Interleucina-33 , Animais , Humanos , Camundongos , Citocinas/metabolismo , Fibrose , Imunidade Inata , Inflamação , Interleucina-33/metabolismo , Interleucinas , Linfócitos/metabolismo , Interleucina-17/metabolismo
20.
Pathol Oncol Res ; 28: 1610474, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110250

RESUMO

Background: The progression from chronic gastroesophageal reflux disease (GERD) to Barrett esophagus (BE) and esophageal adenocarcinoma (EAC) is an inflammatory-driven neoplastic change. Interleukin-33 (IL-33) has identified as a crucial factor in several inflammatory disorders and malignancies. Methods: The high-density tissue microarray of the human EAC was analyzed with IL-33 immunohistochemistry staining (IHC). By anastomosing the jejunum with the esophagus, the rat model of EAC with mixed gastroduodenal reflux was established. The expression of IL-33 was determined using quantitative real-time polymerase chain reaction (RT-qPCR), western blot (WB), IHC and enzyme-linked immunosorbent assay (ELISA). Esophageal adenocarcinoma cells (OE19 and OE33) and human esophageal epithelial cells (HEECs) were used. Results: In the cytoplasm of human EAC tissue, IL-33 expression was substantially greater than in adjacent normal tissue. In rat model, the expression of IL-33 in the EAC group was considerably greater than in the control group, and this expression increased with the upgrade of pathological stage. In in vitro experiment, the mRNA and protein levels of IL-33 were considerably greater in OE19 and OE33 than in HEECs. The stimulation of IL-33 enhanced the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of OE19 and OE33, but soluble ST2 (sST2) inhibited these effects. IL-33 stimulated the release of IL-6 by OE19 and OE33 cells. Conclusion: This study demonstrated the overexpression of IL-33 in the transition from GERD to EAC and that IL-33 promoted carcinogenesis in EAC cells through ST2. IL-33 might be a possible preventive target for EAC.


Assuntos
Adenocarcinoma , Refluxo Gastroesofágico , Interleucina-33 , Adenocarcinoma/patologia , Animais , Neoplasias Esofágicas , Refluxo Gastroesofágico/metabolismo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/metabolismo , Interleucina-6 , RNA Mensageiro , Ratos
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