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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
Front Immunol ; 15: 1447431, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39211040

RESUMO

Mammalian interleukin-22 (IL-22) attenuates organismal injury by inhibiting reactive oxygen species (ROS) and impeding the NLRP3 inflammasome activation. However, the role of fish IL-22 in this process remains unclear. We characterized MaIL-22, an IL-22 homolog in blunt snout bream (Megalobrama amblycephala). Despite its low sequence identity, it shares conserved structures and close evolutionary relationships with other teleost IL-22s. Furthermore, Aeromonas hydrophila (A. hydrophila) infection leads to tissue injury in M. amblycephala immune organs and concomitantly altered Mail-22 mRNA expression, suggesting that MaIL-22 was involved in the antimicrobial immune response. To explore MaIL-22's biological functions, we produced recombinant MaIL-22 (rMaIL-22) protein and demonstrated it significantly enhanced the survival of M. amblycephala post-A. hydrophila infection. To unravel its protective mechanisms, we explored the ROS/NLRP3 inflammasome axis and its downstream signaling responses. The results showed that rMaIL-22 treatment significantly elevated antioxidant enzyme (T-SOD, CAT and GSH-PX) activities to inhibit MDA activity and scavenge ROS in visceral tissues. Meanwhile, rMaIL-22 impeded the activation of NLRP3 inflammasome by suppressing NLRP3 protein and mRNA expression. This indicated that rMaIL-22 contributed to inhibit A. hydrophila-induced activation of the ROS/NLRP3 inflammasome axis. Consistent with these findings, rMaIL-22 treatment attenuated the expression of proinflammatory cytokines (il-1ß, tnf-α and il-6) and proapoptotic genes (caspase-3 and caspase-8) while promoting antiapoptotic genes (bcl-2b and mcl-1a) expression, ultimately mitigating tissue injury in visceral tissues. In conclusion, our research underscores MaIL-22's key role in microbial immune regulation, offering insights for developing IL-22-targeted therapies and breeding programs.


Assuntos
Aeromonas hydrophila , Apoptose , Doenças dos Peixes , Infecções por Bactérias Gram-Negativas , Inflamassomos , Inflamação , Interleucina 22 , Interleucinas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio , Animais , Aeromonas hydrophila/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Inflamassomos/imunologia , Apoptose/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/imunologia , Espécies Reativas de Oxigênio/metabolismo , Interleucinas/metabolismo , Interleucinas/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Inflamação/imunologia , Proteínas de Peixes/metabolismo , Proteínas de Peixes/imunologia , Proteínas de Peixes/genética , Cyprinidae/imunologia , Cyprinidae/metabolismo , Transdução de Sinais
10.
Front Immunol ; 15: 1437224, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39211051

RESUMO

IL-32 expression is important for pathogen clearance but detrimental in chronic inflammation, autoimmunity, and cancer. T cells are major IL-32 producers in these diseases and key mediators of pathogen and tumor elimination but also autoimmune destruction. However, their contribution to IL-32 biology during immune responses is hardly understood due to several isoforms with divergent inflammatory properties. Here, we identified IL-32ß as the predominant isoform in various T cell subsets of healthy individuals and breast cancer patients with the highest levels detected in intratumoral regulatory T cells. We show that IL-32ß is induced by IL-2 but IL-32ß release requires T Cell Receptor rather than IL2R stimulation. Using inhibitors of protein secretion pathways and serial (ultra)centrifugation of T cell supernatants, we demonstrate that T cells actively secrete IL-32ß unconventionally, as a free protein and, to a minor degree, through exosomes. Thus, our data identify activated T cells as major IL-32ß secretors in health and cancer.


Assuntos
Neoplasias da Mama , Interleucina-2 , Interleucinas , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Humanos , Interleucinas/metabolismo , Interleucina-2/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Feminino , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
11.
Cancer Cell ; 42(8): 1450-1466.e11, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39137729

RESUMO

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.


Assuntos
Neoplasias Encefálicas , Proteína delta de Ligação ao Facilitador CCAAT , Glioblastoma , Interleucinas , Células Matadoras Naturais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Glioblastoma/imunologia , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Interleucinas/genética , Interleucinas/metabolismo , Interleucinas/imunologia , Humanos , Animais , Camundongos , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Interleucina-15/genética , Interleucina-15/metabolismo , Interleucina-15/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(4): 1197-1200, 2024 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-39192419

RESUMO

OBJECTIVE: To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-ß and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. METHODS: 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-ß and IL-10 in serum, and their differences between different groups were compared. RESULTS: Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-ß, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). CONCLUSION: The decrease of Tregs, IL-35, TGF-ß, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.


Assuntos
Hemofilia A , Interleucina-10 , Interleucinas , Linfócitos T Reguladores , Fator de Crescimento Transformador beta , Humanos , Interleucina-10/sangue , Hemofilia A/sangue , Fator de Crescimento Transformador beta/sangue , Interleucinas/sangue , Masculino , Estudos de Casos e Controles , Relevância Clínica
13.
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
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.
Adv Clin Exp Med ; 33(8): 889-899, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39194161

RESUMO

BACKGROUND: T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses, but the functional role of Tfh cells in the pathogenesis of idiopathic membranous nephropathy (IMN) remains unclear. OBJECTIVES: This study aimed to establish a rat experimental membranous nephropathy model, investigate the phenotypic characteristics of Tfh cells, and analyze a clinically significant correlation between Tfh cells. MATERIAL AND METHODS: Passive Heymann nephritis (PHN) rats were induced by immunizing Sprague Dawley rats with anti-Fx1A serum. The frequency of Tfh and B cell subsets was analyzed with flow cytometry (FC). The serum concentration of interleukin-21 (IL-21), the relative mRNA expression levels of IL-21 and B cell lymphoma 6 (Bcl-6) in spleen mononuclear cells (MNCs), and the kidney infiltration of CD4+ T cells and IL-21 were assessed. The potential correlations among these measures were analyzed. RESULTS: In comparison with the control group, significantly increased percentages of Tfh cells, inducible T cell co-stimulator-positive (ICOS+) Tfh cells, and mRNA expression of Bcl-6 were detected in the spleen of PHN rats. Elevated IL-21 expression was detected in the serum and kidneys. Remarkably, the percentage of splenic ICOS+ Tfh cells was positively correlated with 24 h urine protein concentrations (r = 0.676, p = 0.011) in PHN rats. CONCLUSION: These data indicate that ICOS+ Tfh cells contribute to development of IMN, and they might be potential therapeutic targets for IMN.


Assuntos
Modelos Animais de Doenças , Progressão da Doença , Glomerulonefrite Membranosa , Interleucinas , Proteínas Proto-Oncogênicas c-bcl-6 , Ratos Sprague-Dawley , Células T Auxiliares Foliculares , Animais , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/sangue , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/metabolismo , Ratos , Interleucinas/sangue , Interleucinas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Masculino , Baço/imunologia , Baço/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
16.
Int J Mol Sci ; 25(15)2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39125732

RESUMO

Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients.


Assuntos
Neoplasias Ósseas , Interleucinas , Microambiente Tumoral , Humanos , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Interleucinas/metabolismo , Animais , Transdução de Sinais
17.
Int J Mol Sci ; 25(15)2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39126011

RESUMO

The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.


Assuntos
Dermatite Atópica , Interleucina-13 , Interleucinas , Prurigo , Prurido , Humanos , Dermatite Atópica/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dermatite Atópica/imunologia , Prurigo/metabolismo , Prurigo/patologia , Prurigo/genética , Feminino , Adulto , Masculino , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucinas/metabolismo , Interleucinas/genética , Prurido/metabolismo , Prurido/genética , Pessoa de Meia-Idade , Interleucina-4/metabolismo , Interleucina-4/genética , Doença Crônica , Pele/metabolismo , Pele/patologia , Adulto Jovem , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/genética
18.
Clin Exp Med ; 24(1): 184, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39117877

RESUMO

The prevalence of HCV infection in Egypt has decreased following the introduction of direct-acting antiviral therapy. However, treatment response is influenced by various factors, particularly host immunogenetics such as IL-28B and FOXP3 polymorphisms. The current study examined the impact of SNPs in the FOXP3 gene promoter region on HCV-infected Egyptian patients, along with SNPs in the IL28B gene.This study involved 99 HCV patients who achieved SVR12 after a 12 week DAA treatment while 63 HCV patients experienced treatment failure. IL28B rs12979860 SNP was identified using real-time PCR, while IL28B rs8099917, FOXP3 rs3761548, and rs2232365 SNPs were analyzed using RFLP-PCR. Serum levels of IL28B and FOXP3 were quantified using ELISA technique in representative samples from both groups. The IL28B rs12979860 T > C (P = 0.013) and FOXP3 rs2232365 A > G polymorphisms (P = 0.008) were found to significantly increase the risk of non-response. Responders had higher IL28B serum levels (P = 0.046) and lower FOXP3 levels (P < 0.001) compared to non-responders. Regression analysis showed an association between IL28B rs12979860 and FOXP3 rs2232365 with treatment response, independent of age and gender. A predictive model was developed with 76.2% sensitivity and 91.9% specificity for estimating DAAs response in HCV patients.Our findings confirmed the IL28B rs12979860 T > C and FOXP3 rs2232365 A > G polymorphisms significantly affect DAA treatment response in HCV Egyptian patients. Lower levels of IL-28B along with higher levels of FOXP3 are linked to poor response. Our results may lead to new insights into DAA responsiveness contributing to personalized medicine and improving therapeutic decision-making for HCV patients.


Assuntos
Antivirais , Fatores de Transcrição Forkhead , Hepatite C Crônica , Interferons , Interleucinas , Polimorfismo de Nucleotídeo Único , Humanos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Masculino , Feminino , Antivirais/uso terapêutico , Pessoa de Meia-Idade , Interleucinas/genética , Interleucinas/sangue , Adulto , Egito , Fatores de Transcrição Forkhead/genética , Resultado do Tratamento , Regiões Promotoras Genéticas , Imunogenética , Interferon lambda
19.
Medicine (Baltimore) ; 103(32): e39036, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39121248

RESUMO

The association between interleukins and osteoporosis has attracted much attention these days. However, the causal relationship between them is uncertain. Hence, this study performed a Mendelian randomization (MR) analysis to investigate the causal effects of interleukins on osteoporosis. The summary data for interleukins and osteoporosis came from 4 different genome-wide association studies. Significant and independent (P < 5 × 10-6; r2 < 0.001, 10,000 kbp) single-nucleotide polymorphisms were extracted for MR analysis. The inverse-variance weighted and other methods were used for MR analysis, while sensitivity analyses were conducted to test the reliability and stability. The positive causal effects of interleukin-7 on osteoporosis (odds ratio = 1.084; 95% confidence interval: 1.010-1.163; P = .025) were observed. No causal relationship was found between other interleukins and osteoporosis. In the sensitivity analysis, the results did not show the presence of pleiotropy and heterogeneity. Therefore, the results were robust for the MR analysis. This study revealed that interleukin-7 was positively related to osteoporosis and that other interleukins were not related to osteoporosis.


Assuntos
Estudo de Associação Genômica Ampla , Interleucinas , Análise da Randomização Mendeliana , Osteoporose , Polimorfismo de Nucleotídeo Único , Humanos , Osteoporose/genética , Interleucinas/genética , Interleucina-7/genética , Predisposição Genética para Doença
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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