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1.
Sci Rep ; 14(1): 21351, 2024 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266694

RESUMO

In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients' cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples.


Assuntos
Febre Familiar do Mediterrâneo , Interleucina-23 , Interleucinas , Humanos , Feminino , Masculino , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/imunologia , Interleucinas/sangue , Interleucina-23/sangue , Adulto , Adulto Jovem , Estudos de Casos e Controles , Células Th17/imunologia , Células Th17/metabolismo , Citocinas/sangue
2.
Cells ; 13(17)2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39273061

RESUMO

Zika virus (ZIKV) is an arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV triggers an immune defense in the placenta. This immune response counts with the participation of interleukins and transcription factors. Additionally, it has the potential involvement of human endogenous retroviruses (HERVS). Interleukins are immune response regulators that aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. HERVs are remnants of ancient viral infections that integrate into the genome and produce syncytin proteins crucial for placental development. Since ZIKV can infect trophoblast cells, we analyzed the relationship between ZIKV infection, HERV, interleukin, and transcription factor modulations in the placenta. To investigate the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asian-Brazilian) using Taqman and RT2 Profiler PCR Array assays. Our results indicate that early ZIKV infection (24-72 h) does not induce differential interleukins, transcription factors, and HERV expression. However, we show that the expression of a few of these host defense genes appears to be linked independently of ZIKV infection. Future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and transcription factors in the placenta.


Assuntos
Retrovirus Endógenos , Interleucinas , Fatores de Transcrição , Trofoblastos , Infecção por Zika virus , Zika virus , Humanos , Trofoblastos/virologia , Trofoblastos/metabolismo , Feminino , Infecção por Zika virus/virologia , Infecção por Zika virus/genética , Retrovirus Endógenos/genética , Gravidez , Interleucinas/genética , Interleucinas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Placenta/virologia , Placenta/metabolismo , Linhagem Celular
3.
Nat Commun ; 15(1): 7662, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266531

RESUMO

Most patients with advanced cancer develop cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting. Despite its catastrophic impact on survival, the critical mediators responsible for cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in the advanced cancer milieu and promotes skeletal muscle loss. Unbiased transcriptome analysis reveals that interleukin 36 gamma (IL36G)-producing CD38+ CiMs are induced in chronic monocytic blood cancer characterized by prominent cachexia. Notably, the emergence of CiMs and the activation of CiM-related gene signatures in monocytes are confirmed in various advanced solid cancers. Stimuli of toll-like receptor 4 signaling are responsible for the induction of CiMs. Genetic inhibition of IL36G-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models. These findings indicate that the IL36G-producing subset of neutrophil-like monocytes could be a potential therapeutic target in cancer cachexia.


Assuntos
Caquexia , Monócitos , Músculo Esquelético , Neoplasias , Neutrófilos , Caquexia/metabolismo , Caquexia/etiologia , Monócitos/metabolismo , Monócitos/imunologia , Humanos , Neoplasias/complicações , Neoplasias/metabolismo , Neoplasias/imunologia , Neutrófilos/metabolismo , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Camundongos , Masculino , Transdução de Sinais , Linhagem Celular Tumoral , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Camundongos Endogâmicos C57BL , Interleucinas/metabolismo , Interleucinas/genética , Feminino , Perfilação da Expressão Gênica
4.
Med Oncol ; 41(10): 240, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39231878

RESUMO

Interleukin-22, discovered in the year of 2000, is a pleiotropic Th17 cytokine from the IL-10 family of cytokines. IL-22 signals through the type 2 cytokine receptor complex IL-22R and predominantly activates STAT3. This pathway leads to the transcription of several different types of genes, giving IL-22 context-specific functions ranging from inducing antimicrobial peptide expression to target cell proliferation. In recent years, it has been shown that IL-22 is involved in the pathogenesis of neoplasia in some cancers through its pro-proliferative and anti-apoptotic effects. This review highlights studies with recent discoveries and conclusions drawn on IL-22 and its involvement and function in various cancers. Such a study may be helpful to better understand the role of IL-22 in cancer so that new treatment could be developed targeting IL-22.


Assuntos
Interleucina 22 , Interleucinas , Neoplasias , Humanos , Interleucinas/metabolismo , Neoplasias/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Animais , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética
5.
Appl Microbiol Biotechnol ; 108(1): 469, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39298023

RESUMO

Prior research has indicated that the gut-lung-axis can be influenced by the intestinal microbiota, thereby impacting lung immunity. Rifaximin is a broad-spectrum antibacterial drug that can maintain the homeostasis of intestinal microflora. In this study, we established an influenza A virus (IAV)-infected mice model with or without rifaximin supplementation to investigate whether rifaximin could ameliorate lung injury induced by IAV and explore the molecular mechanism involved. Our results showed that IAV caused significant weight loss and disrupted the structure of the lung and intestine. The analysis results of 16S rRNA and metabolomics indicated a notable reduction in the levels of probiotics Lachnoclostridium, Ruminococcaceae_UCG-013, and tryptophan metabolites in the fecal samples of mice infected with IAV. In contrast, supplementation with 50 mg/kg rifaximin reversed these changes, including promoting the repair of the lung barrier and increasing the abundance of Muribaculum, Papillibacter and tryptophan-related metabolites content in the feces. Additionally, rifaximin treatment increased ILC3 cell numbers, IL-22 level, and the expression of RORγ and STAT-3 protein in the lung. Furthermore, our findings demonstrated that the administration of rifaximin can mitigate damage to the intestinal barrier while enhancing the expression of AHR, IDO-1, and tight junction proteins in the small intestine. Overall, our results provided that rifaximin alleviated the imbalance in gut microbiota homeostasis induced by IAV infection and promoted the production of tryptophan-related metabolites. Tryptophan functions as a signal to facilitate the activation and movement of ILC3 cells from the intestine to the lung through the AHR/STAT3/IL-22 pathway, thereby aiding in the restoration of the barrier. KEY POINTS: • Rifaximin ameliorated IAV infection-caused lung barrier injury and induced ILC3 cell activation. • Rifaximin alleviated IAV-induced gut dysbiosis and recovered tryptophan metabolism. • Tryptophan mediates rifaximin-induced ILC3 cell activation via the AHR/STAT3/IL-22 pathway.


Assuntos
Microbioma Gastrointestinal , Vírus da Influenza A , Pulmão , Infecções por Orthomyxoviridae , Rifaximina , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Rifaximina/uso terapêutico , Camundongos , Pulmão/microbiologia , Pulmão/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Vírus da Influenza A/efeitos dos fármacos , Modelos Animais de Doenças , RNA Ribossômico 16S/genética , Interleucinas/metabolismo , Interleucinas/genética , Interleucina 22 , Camundongos Endogâmicos C57BL , Antibacterianos/farmacologia , Fator de Transcrição STAT3/metabolismo , Fezes/microbiologia , Triptofano/metabolismo , Lesão Pulmonar/tratamento farmacológico , Probióticos/administração & dosagem , Probióticos/farmacologia
6.
Exp Dermatol ; 33(9): e15177, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39304339

RESUMO

Efficacy and safety of ritlecitinib (an oral JAK3/TEC family kinase inhibitor) were evaluated in patients with nonsegmental vitiligo (NSV) across Fitzpatrick skin types (FSTs). Patients with FST I-III ('light skin'; n = 247) and FST IV-VI ('dark skin'; n = 117) received once-daily ritlecitinib 50 mg (with/without 4-week loading dose), low-dose ritlecitinib or placebo for 24 weeks. At baseline, patients with light skin displayed higher CLM-1 and NCR1 serum levels than patients with dark skin (p < 0.05). At 24 weeks, ritlecitinib 50 mg improved the extent of depigmentation measured by percent change from baseline in facial-vitiligo area scoring index (placebo-adjusted mean difference [90% CI]) in patients with light (-15.2 [-24.7, -5.8]; p = 0.004) and dark (-37.4 [-50.3, -24.4]; p < 0.0001) skin, with continuous re-pigmentation through week 48. Treatment-emergent adverse events were similar across FSTs. At weeks 4 and 24, ritlecitinib 50 mg reduced CXCL11 serum levels (p < 0.001) in patients with light skin, whereas patients with dark skin had increased levels at week 4 (p = 0.05) and no significant change at week 24. Ritlecitinib 50 mg decreased IL-9 and IL-22 expression levels in dark skin compared with light skin (qPCR; p < 0.05). These differences in immune dysregulations may explain why NSV patients with dark skin respond to therapy earlier than patients with light skin.


Assuntos
Biomarcadores , Vitiligo , Humanos , Vitiligo/tratamento farmacológico , Vitiligo/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Pigmentação da Pele/efeitos dos fármacos , Adulto , Interleucinas/metabolismo , Interleucinas/sangue , Resultado do Tratamento , Método Duplo-Cego , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Interleucina 22
7.
Front Immunol ; 15: 1444045, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39229279

RESUMO

Introduction: Colitis is an inflammatory bowel disease (IBD) characterized by immune cell dysregulation and alterations in the gut microbiome. In our previous report, we showed a natural product in cruciferous vegetables and ligand of the aryl hydrocarbon receptor (AhR), indole-3-carbinol (I3C), was able to reduce colitis-induced disease severity and microbial dysbiosis in an interleukin-22 (IL-22) dependent manner. Methods: In the current study, we performed single-cell RNA sequencing (scRNAseq) from colonocytes during colitis induction and supplementation with I3C and show how this treatment alters expression of genes involved in IL-22 signaling. To further define the role of IL-22 signaling in I3C-mediated protection during colitis and disease-associated microbial dysbiosis, we generated mice with AhR deficiency in RAR-related orphan receptor c (Rorc)-expressing cells (AhR ΔRorc ) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhR ΔRorc , and littermate (LM) mice with or without I3C treatment. Results: Results showed AhR ΔRorc mice lost the efficacy effects of I3C treatment which correlated with a loss of ability to increase IL-22 by innate lymphoid type 3 (ILC3s), not T helper 22 (Th22) cells. 16S rRNA microbiome profiling studies showed AhR ΔRorc mice were unable to regulate disease-associated increases in Bacteroides, which differed between males and females. Lastly, inoculation with a specific disease-associated Bacteroides species, Bacteroides acidifaciens (B. acidifaciens), was shown to exacerbate colitis in females, but not males. Discussion: Collectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.


Assuntos
Bacteroides , Colite , Interleucina 22 , Interleucinas , Receptores de Hidrocarboneto Arílico , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Animais , Interleucinas/metabolismo , Colite/imunologia , Colite/microbiologia , Feminino , Camundongos , Masculino , Bacteroides/imunologia , Microbioma Gastrointestinal/imunologia , Disbiose/imunologia , Camundongos Endogâmicos C57BL , Indóis/farmacologia , Modelos Animais de Doenças , Fatores Sexuais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos Knockout
8.
Ann Clin Lab Sci ; 54(4): 504-509, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39293844

RESUMO

OBJECTIVE: Chlamydia pneumoniae (C. pneumoniae) is a gram-negative intracellular bacterium that causes respiratory infections in humans. C. pneumoniae is responsible for cell activation and production of cytokines that may contribute to inflammatory responses in asthma. Cell-mediated immune responses are important for protective immunity; however, these responses may be impaired in asthma. In this study, we examined cytokine responses (IL-21, IL-12, IL-13) responsible for T helper (Th)1 versus Th2 responses in C. pneumoniae-stimulated PBMC from subjects with or without asthma. These cytokines could be potential biomarkers in the evaluation of past C. pneumoniae infection. METHODS: Peripheral blood mononuclear cells (PBMC) (1×106/mL) from stable adult asthmatic (N=6) and non-asthmatic subjects (N=6) were infected +/- C. pneumoniae TW-183 at a multiplicity of infection (MOI)=0.1, using dose responses (1:10, 1:100), and cultured 48 hrs. Cytokine responses (Interleukin (IL)-21, IL-12, IL-13) were measured in supernatants (ELISA). RESULTS: Cytokine responses (mean differences: unstimulated-stimulated cells) were significant for IL-12 (1:10, 1:100) (P=0.0005, 0.0005) but not for IL-21 or IL-13 (Wilcoxon signed-rank test). Cytokine levels were higher in asthmatic subjects for IL-13 (mean differences: non-asthma-asthma) (unstimulated, 1:10, 1:100) (-210±167, -140±113, -89±59, respectively) (P=0.05, 0.05, 0.05, respectively) compared with non-asthma. However, IL-21 and IL-12 responses were similar in both groups. When subjects were stratified according to C. pneumoniae IgG antibody status, no significant differences in cytokine responses were observed. CONCLUSION: Differential cytokine patterns in subjects with or without asthma may suggest a mechanism for the development of persistent infection with C. pneumoniae.


Assuntos
Asma , Chlamydophila pneumoniae , Interleucina-12 , Interleucina-13 , Interleucinas , Leucócitos Mononucleares , Humanos , Asma/imunologia , Asma/microbiologia , Chlamydophila pneumoniae/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Interleucina-12/metabolismo , Adulto , Masculino , Feminino , Interleucinas/metabolismo , Interleucina-13/metabolismo , Pessoa de Meia-Idade , Citocinas/metabolismo , Células Th2/imunologia
9.
Int Ophthalmol ; 44(1): 379, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39292290

RESUMO

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is an autoimmune condition commonly linked with Graves' disease (GD), characterized by orbital tissue inflammation and fibrosis. It is hypothesized that gene polymorphisms may influence production of the IL-17 and IL-38 cytokines, thereby impacting TAO development and progression. This study focused on investigating the gene polymorphisms of IL-17 (rs9463772 C/T in IL17F) and IL-38 (rs3811058 C/T, rs7570267 A/G in IL1F10) in patients with GD. METHODS: A case-control study was conducted on 132 patients with TAO and 153 patients without TAO according to eligibility criteria. After clinical examination blood samples were collected for further investigations. Genotyping was performed with the TaqMan™ Master Mix kit. Allele and genotype frequencies were compared between studied groups and subgroups. RESULTS: No significant differences were found in age, duration of GD, or thyroid hormone between patients with and without TAO. However, a higher predisposition to develop TAO was observed among smokers (OR = 1.682, p = 0.03). Overall, no significant associations between gene polymorphisms and TAO development were identified in GD patients. Further analysis revealed that the CC genotype in IL1F10 rs3811058 polymorphism among Caucasians was associated with an increased risk of TAO (OR = 2.7, p = 0.02), as well as allele differences were also significant (OR = 2.8, p = 0.001). CONCLUSIONS: These findings shed light on TAO genetic predispositions in Kazakhstani GD patients, notably among Caucasians, underscoring the need for further research. These results may offer valuable targets for the development of novel treatments for TAO.


Assuntos
Predisposição Genética para Doença , Genótipo , Oftalmopatia de Graves , Interleucina-17 , Interleucinas , Polimorfismo de Nucleotídeo Único , Humanos , Oftalmopatia de Graves/genética , Oftalmopatia de Graves/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos de Casos e Controles , Interleucina-17/genética , Interleucinas/genética , Frequência do Gene , DNA/genética , Alelos
10.
Allergol Immunopathol (Madr) ; 52(5): 94-102, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39278858

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective antibody production and impaired differentiation of B cells. B cell proliferation is an essential step for antibody synthesis. Depending on the nature of the stimulus, their response may be either T-cell-dependent or T-cell-independent. METHODS: We studied 23 CVID patients and 14 healthy donors (HD). The patients were categorized based on their percentage of memory B cells. In addition to standard immunophenotyping of circulating human B and T cell subsets, an in vitro CFSE dilution assay was used to assess the proliferative capacity of B cells and to compare the activation of the T cell-dependent and T cell-independent response among the patients. RESULTS: Patients with a reduction in memory B cells exhibited an increase in follicular T cells (Tfh) and showed low proliferation in response to PKW, CpG, and SAC stimuli (Condition II) (p= 0.0073). In contrast, patients with a normal percentage of memory B cells showed a high expression of IL-21R and low proliferation in response to CPG (Condition III); IL-21, CD40L, and anti-IgM (Condition IV) stimuli (p= 0.0163 and p = 0.0475, respectively). CONCLUSION: Defective proliferation in patients depends on the type of stimulus used and the phenotypic characteristics of the patients. Further studies are necessary to understand the disease mechanisms, which may guide us toward identifying genetic defects associated with CVID.


Assuntos
Proliferação de Células , Imunodeficiência de Variável Comum , Ativação Linfocitária , Humanos , Imunodeficiência de Variável Comum/imunologia , Masculino , Feminino , Adulto , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Imunofenotipagem , Linfócitos B/imunologia , Adulto Jovem , Células Cultivadas , Células B de Memória/imunologia , Interleucinas/metabolismo , Interleucinas/imunologia , Adolescente , Memória Imunológica/imunologia
11.
Front Immunol ; 15: 1402834, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39253083

RESUMO

Introduction: Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. Methods: To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Results: Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Discussion: Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.


Assuntos
Citrobacter rodentium , Colite , Infecções por Enterobacteriaceae , Imunidade Inata , Interleucina 22 , Interleucinas , Linfócitos , Camundongos Knockout , Sirtuínas , Animais , Camundongos , Linfócitos/imunologia , Linfócitos/metabolismo , Interleucinas/metabolismo , Interleucinas/imunologia , Interleucinas/genética , Sirtuínas/genética , Sirtuínas/metabolismo , Colite/imunologia , Colite/induzido quimicamente , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos C57BL , Sulfato de Dextrana , Modelos Animais de Doenças
12.
Front Immunol ; 15: 1441908, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224597

RESUMO

Introduction: The antiviral activity of recombinant bovine interferon lambda 3 (bovIFN-λ3) against bovine viral diarrhea virus (BVDV) has been demonstrated in vitro in Madin-Darby bovine kidney cells (MDBK) and in vivo in cattle. However, anti-BVDV activity of bovIFN-λ3 has not been studied in bovine respiratory tract epithelial cells, supposedly a primary target of BVDV infection when entering the host by the oronasal route. Methods: Here we investigated the anti-BVDV activity of bovIFN-λ3 in bovine turbinate-derived primary epithelial cells (BTu) using BVDV infection and immunoperoxidase staining, TCID50, RT-qPCR, DNA and transcriptome sequencing, and transfection with plasmids containing the two subunits, IL-28Rα and IL-10Rß that constitute the bovIFN-λ3 receptor. Results: Our immunoperoxidase staining, RT-qPCR, and TCID50 results show that while BVDV was successfully cleared in MDBK cells treated with bovIFN-λ3 and bovIFN-α, only the latter, bovIFN-α, cleared BVDV in BTu cells. Preincubation of MDBK cells with bovIFN-λ3 before BVDV infection was needed to induce optimal antiviral state. Both cell types displayed intact type I and III IFN signaling pathways and expressed similar levels of IL-10Rß subunit of the type III IFN receptor. Sequencing of PCR amplicon of the IL-28Rα subunit revealed intact transmembrane domain and lack of single nucleotide polymorphisms (SNPs) in BTu cells. However, RT-qPCR and transcriptomic analyses showed a lower expression of IL-28Rα transcripts in BTu cells as compared to MDBK cells. Interestingly, transfection of BTu cells with a plasmid encoding IL-28Rα subunit, but not IL-10Rß subunit, established the bovIFN-λ3 sensitivity showing similar anti-BVDV activity to the response in MDBK cells. Conclusion: Our results demonstrate that the sensitivity of cells to bovIFN-λ3 depends not only on the quality but also of the quantity of the IL-28Rα subunit of the heterodimeric receptor. A reduction in IL-28Rα transcript expression was detected in BTu as compared to MDBK cells, despite the absence of spliced variants or SNPs. The establishment of bovIFN-λ3 induced anti-BVDV activity in BTu cells transfected with an IL-28Rα plasmid suggests that the level of expression of this receptor subunit is crucial for the specific antiviral activity of type III IFN in these cells.


Assuntos
Interferon lambda , Interferons , Conchas Nasais , Animais , Bovinos , Interferons/metabolismo , Interferons/imunologia , Conchas Nasais/virologia , Conchas Nasais/imunologia , Conchas Nasais/metabolismo , Antivirais/farmacologia , Vírus da Diarreia Viral Bovina/imunologia , Vírus da Diarreia Viral Bovina/fisiologia , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Células Epiteliais/virologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Interleucinas/genética , Interleucinas/farmacologia , Interleucinas/imunologia , Interleucinas/metabolismo , Linhagem Celular , Doença das Mucosas por Vírus da Diarreia Viral Bovina/imunologia , Doença das Mucosas por Vírus da Diarreia Viral Bovina/virologia , Proteínas Recombinantes/farmacologia , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/metabolismo , Receptores de Citocinas
13.
Brain Behav Immun ; 122: 287-300, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39097202

RESUMO

Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.


Assuntos
Interleucinas , Microglia , Neuralgia , Traumatismos dos Nervos Periféricos , Animais , Masculino , Microglia/metabolismo , Microglia/efeitos dos fármacos , Camundongos , Neuralgia/metabolismo , Neuralgia/tratamento farmacológico , Interleucinas/metabolismo , Feminino , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/complicações , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Inflamação/metabolismo
14.
Korean J Gastroenterol ; 84(2): 65-81, 2024 Aug 25.
Artigo em Coreano | MEDLINE | ID: mdl-39176462

RESUMO

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.


Assuntos
Anticorpos Monoclonais Humanizados , Produtos Biológicos , Doenças Inflamatórias Intestinais , Interleucinas , Humanos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Interleucinas/metabolismo , Ustekinumab/uso terapêutico
15.
Cells ; 13(16)2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39195286

RESUMO

Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin condition characterized by a multifaceted pathophysiology that gives rise to diverse clinical manifestations. The management of AD remains challenging due to the suboptimal efficacy of existing treatment options. Nonetheless, recent progress in elucidating the underlying mechanisms of the disease has facilitated the identification of new potential therapeutic targets and promising drug candidates. In this review, we summarize the newest data, considering multiple connections between IL-22 and AD. The presence of circulating IL-22 has been found to correlate with the severity of AD and is identified as a critical factor driving the inflammatory response associated with the condition. Elevated levels of IL-22 in patients with AD are correlated with increased proliferation of keratinocytes, alterations in the skin microbiota, and impaired epidermal barrier function. Collectively, these factors contribute to the manifestation of the characteristic symptoms observed in AD.


Assuntos
Dermatite Atópica , Interleucina 22 , Interleucinas , Dermatite Atópica/patologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Humanos , Interleucinas/metabolismo , Animais , Queratinócitos/metabolismo , Pele/patologia , Pele/metabolismo , Microbiota
16.
Dev Comp Immunol ; 161: 105249, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39154973

RESUMO

IL-26 is a cytokine that is crucial for the maintenance and function of the gut mucosal barrier. IL-26 signaling pathway relies on a heterodimeric receptor complex, which is composed of two distinct subunits, IL-10R2 and IL-20R1. However, there are no reports on the antibacterial immunity of IL-26 and its receptors in fish. For this purpose, in this study we identified IL-26 and its receptors IL-10R2 and IL-20R1 in Carassius cuvieri × Carassius auratus red var. (named WR-IL-26, WR-IL10R2 and WR-IL20R1, respectively). Phylogenetic analysis confirmed the conservation of these genes, with shared structural motifs similar to those found in higher vertebrates. Upon exposure to Aeromonas hydrophila, a common fish pathogen, there was a significant upregulation of WR-IL-26, WR-IL10R2 and WR-IL20R1 in the gut, indicating a potential role in the immune response to infection. A co-immunoprecipitation assay revealed that WR-IL-26 formed complexes with WR-IL10R2 and WR-IL20R1. In vivo experiments demonstrated that administration of WR-IL-26 activated the JAK1-STAT3 signaling pathway and protected the gut mucosa barrier from A. hydrophila infection. Conversely, silencing WR-IL10R2 and WR-IL20R1 via RNA interference significantly attenuated the activation of WR-IL-26-mediated JAK1-STAT3 pathway. These results provided new insights into the role of IL-26 and its receptors in the gut mucosa barrier and could offer novel therapeutic strategies for managing bacterial infections in aquaculture.


Assuntos
Aeromonas hydrophila , Doenças dos Peixes , Proteínas de Peixes , Imunidade Inata , Interleucinas , Mucosa Intestinal , Receptores de Interleucina , Transdução de Sinais , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteínas de Peixes/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Aeromonas hydrophila/imunologia , Aeromonas hydrophila/fisiologia , Interleucinas/metabolismo , Interleucinas/imunologia , Interleucinas/genética , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Doenças dos Peixes/imunologia , Transdução de Sinais/imunologia , Filogenia , Infecções por Bactérias Gram-Negativas/imunologia , Carpa Dourada/imunologia , Imunidade nas Mucosas , Subunidade beta de Receptor de Interleucina-10/metabolismo , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/imunologia
17.
Fish Shellfish Immunol ; 153: 109838, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39151839

RESUMO

IL-26 is a crucial inflammatory cytokine that participates in defending host cells against infections. We initially cloned and identified the cDNA sequences of interleukin (IL)-26 in channel catfish (Ictalurus punctatus). The open reading frame (ORF) of IpIL-26 was 537 bp in length, encoding 178 amino acids (aa). Constitutive expression of IpIL-26 was observed in tested tissues, with the highest level found in the gill and spleen. To explore the function of IpIL-26 in channel catfish, different stimuli were used to act on both channel catfish and channel catfish kidney cells (CCK). The expression of IpIL-26 could be up-regulated by bacteria and viruses in multiple tissues. In vitro, recombinant IpIL-26 (rIpIL-26) could induce the expression levels of inflammatory cytokines such as TNF-α, IL-1ß, IL-6, IL-20, and IL-22 playing vital roles in defending the host against infections. Our results demonstrated that IpIL-26 might be an essential cytokine, significantly affecting the immune defense of channel catfish against pathogen infections.


Assuntos
Sequência de Aminoácidos , Doenças dos Peixes , Proteínas de Peixes , Regulação da Expressão Gênica , Ictaluridae , Imunidade Inata , Interleucinas , Filogenia , Alinhamento de Sequência , Animais , Ictaluridae/imunologia , Ictaluridae/genética , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Proteínas de Peixes/química , Interleucinas/genética , Interleucinas/imunologia , Imunidade Inata/genética , Doenças dos Peixes/imunologia , Alinhamento de Sequência/veterinária , Regulação da Expressão Gênica/imunologia , Perfilação da Expressão Gênica/veterinária , Sequência de Bases , DNA Complementar/genética
18.
Int Immunopharmacol ; 141: 112966, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39178518

RESUMO

Extracellular matrix (ECM) metabolism disorders in the inflammatory microenvironment play a key role in the pathogenesis of intervertebral disc degeneration (IDD). Interleukin-32 (IL-32) has been reported to be involved in the progression of various inflammatory diseases; however, it remains unclear whether it participates in the matrix metabolism of nucleus pulposus (NP) cells. Therefore, this study aimed to investigate the mechanism of IL-32 on regulating the ECM metabolism in the inflammatory microenvironment. RNA-seq was used to identify aberrantly expressed genes in NP cells in the inflammatory microenvironment. Western blotting, real-time quantitative PCR, immunohistochemistry and immunofluorescence analysis were performed to measure the expression of IL-32 and metabolic markers in human NP tissues or NP cells treated with or without tumor necrosis factor-α (TNF-α). In vivo, an adeno-associated virus overexpressing IL-32 was injected into the caudal intervertebral discs of rats to assess its effect on IDD. Proteins interacting with IL-32 were identified via immunoprecipitation and mass spectrometry. Lentivirus overexpressing IL-32 or knocking down Fat atypical cadherin 4 (FAT4), yes-associated protein (YAP) inhibitor-Verteporfin (VP) were used to treat human NP cells, to explore the pathogenesis of IL-32. Hippo/YAP signaling activity was verified in human NP tissues. IL-32 expression was significantly upregulated in degenerative NP tissues, as indicated in the clinical samples. Furthermore, IL-32 was remarkably overexpressed in TNF-α-induced degenerative NP cells. IL-32 overexpression induced IDD progression in the rat model. Mechanistically, the elevation of IL-32 in the inflammatory microenvironment enhanced its interactions with FAT4 and mammalian sterile 20-like kinase1/2 (MST1/2) proteins, prompting MST1/2 phosphorylation, and activating the Hippo/YAP signaling pathway, causing matrix metabolism disorder in NP cells. Our results suggest that IL-32 mediates matrix metabolism disorders in NP cells in the inflammatory micro-environment via the FAT4/MST/YAP axis, providing a theoretical basis for the precise treatment of IDD.


Assuntos
Via de Sinalização Hippo , Interleucinas , Degeneração do Disco Intervertebral , Núcleo Pulposo , Ratos Sprague-Dawley , Transdução de Sinais , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Humanos , Animais , Degeneração do Disco Intervertebral/metabolismo , Interleucinas/metabolismo , Masculino , Ratos , Caderinas/metabolismo , Proteínas de Sinalização YAP/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Serina-Treonina Quinases/metabolismo , Adulto , Células Cultivadas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Pessoa de Meia-Idade , Feminino , Matriz Extracelular/metabolismo
19.
Biochim Biophys Acta Mol Basis Dis ; 1870(8): 167469, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39153664

RESUMO

Premature ovarian insufficiency (POI) critically affects female reproductive health, with obesity being a significant and recognized risk factor. Interleukin-27 (IL-27), known for its role in immune modulation and inflammation, has garnered attention in metabolic syndrome research. Nonetheless, the role of these immunometabolic factors on the initiation of POI remains to be unraveled. Our investigation delves into the influence of impaired IL-27 signaling on POI induction, particularly under the challenge of a high-fat diet (HFD). We analyzed patients' serum profiles and established a correlation of increased serum triglycerides with decreased IL-27 levels in POI cases. Experiments on C57BL/6 mice lacking the IL-27 receptor alpha (Il27ra-/-) revealed that when subjected to HFD, these mice developed hallmark POI symptoms. This includes escalated lipid deposition in both liver and ovarian tissues, increased ovarian macrophages cellular aging, and diminished follicle count, all pointing to compromised ovarian function. These findings unveil a novel pathway wherein impaired IL-27 signaling potentiates the onset of POI in the presence of HFD. Understanding the intricate interplay between IL-27, metabolic alterations, and immune dysregulation sheds light on potential therapeutic avenues for managing POI, offering hope for improved reproductive health outcomes.


Assuntos
Dieta Hiperlipídica , Macrófagos , Insuficiência Ovariana Primária , Receptores de Interleucina , Transdução de Sinais , Adulto , Animais , Feminino , Humanos , Camundongos , Senescência Celular , Dieta Hiperlipídica/efeitos adversos , Interleucinas/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovário/metabolismo , Ovário/patologia , Insuficiência Ovariana Primária/patologia , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/imunologia , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética
20.
Nat Immunol ; 25(9): 1565-1579, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39103576

RESUMO

Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.


Assuntos
Colite , Imunidade nas Mucosas , Camundongos Knockout , Mitocôndrias , Proteínas Nucleares , Nucleofosmina , Fosforilação Oxidativa , Animais , Mitocôndrias/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Humanos , Colite/imunologia , Colite/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Interleucina 22 , Imunidade Inata , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Sulfato de Dextrana , Masculino , Interleucinas/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Feminino
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