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1.
Int J Mol Sci ; 24(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36614224

RESUMO

Atopic dermatitis is a chronic, recurrent inflammatory skin disorder manifesting by eczematous lesions and intense pruritus. Atopic dermatitis develops primarily as a result of an epidermal barrier defect and immunological imbalance. Advances in understanding these pathogenetic hallmarks, and particularly the complex role of interleukins as atopic dermatitis drivers, resulted in achieving significant therapeutic breakthroughs. Novel medications involve monoclonal antibodies specifically blocking the function of selected interleukins and small molecules such as Janus kinase inhibitors limiting downstream signaling to reduce the expression of a wider array of proinflammatory factors. Nevertheless, a subset of patients remains refractory to those treatments, highlighting the complexity of atopic dermatitis immunopathogenesis in different populations. In this review, we address the immunological heterogeneity of atopic dermatitis endotypes and phenotypes and present novel interleukin-oriented therapies for this disease.


Assuntos
Dermatite Atópica , Dermatopatias , Humanos , Dermatite Atópica/patologia , Interleucinas/metabolismo , Prurido/tratamento farmacológico , Pele/metabolismo , Dermatopatias/complicações
2.
Immunity ; 56(1): 125-142.e12, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630911

RESUMO

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.


Assuntos
Neoplasias Hepáticas , Células T Matadoras Naturais , Camundongos , Animais , Células Endoteliais/metabolismo , Interleucinas/metabolismo , Interleucina-17/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL
3.
Immunity ; 56(1): 143-161.e11, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630913

RESUMO

Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.


Assuntos
Interleucinas , Neoplasias , Humanos , Animais , Camundongos , Interleucinas/genética , Interleucinas/metabolismo , Células Matadoras Naturais , Linfócitos T Auxiliares-Indutores , Receptores Virais , Ligação Proteica , Antígenos de Diferenciação de Linfócitos T/metabolismo , Neoplasias/metabolismo
4.
PLoS One ; 18(1): e0280551, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36689413

RESUMO

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy.


Assuntos
Antivirais , Hepatite C Crônica , Humanos , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Interleucinas/genética , Genótipo , Interferons/uso terapêutico , Testes Imediatos
5.
Nutrients ; 15(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615909

RESUMO

We aimed to assess the lipopolysaccharide (LPS), or heat shock (HS) induction, and glutamine-modulating effects on heat shock protein-90α (HSP90α) and cytokines in an ex vivo model using peripheral blood mononuclear cells (PBMCs). The PBMCs of patients with septic shock, trauma-related systemic inflammatory response syndrome (SIRS), and healthy subjects were incubated with 1 µg/mL LPS at 43 °C (HS). Glutamine 10 mM was added 1 hour before or after induction or not at all. We measured mRNA HSP90α, monocyte (m) and lymphocyte (l) HSP90α proteins, interleukin (IL)-1b, -6, -8, -10, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) supernatant levels. Heat shock increased the HSP90α mRNA and mHSP90α in all groups (10-fold in sepsis, p < 0.001 and p = 0.047, respectively). LPS induced the mHSP90α and lHSP90α in healthy (p < 0.001) and mHSP90α in SIRS (p = 0.004) but not in sepsis. LPS induced the cytokines at 24 and 48 h in all groups, especially in trauma (p < 0.001); HS only induced the IL-8 in healthy (p = 0.003) and septic subjects (p = 0.05). Glutamine at 10 mM before or after stimulation did not alter any induction effect of LPS or HS on HSP90α mRNA and mHSP90α protein in sepsis. In SIRS, glutamine before LPS decreased the mHSP90α but increased it when given after HS (p = 0.018). Before or after LPS (p = 0.049) and before HS (p = 0.018), glutamine decreased the lHSP90α expression in sepsis but increased it in SIRS when given after HS (p = 0.003). Regarding cytokines, glutamine enhanced the LPS-induced MCP-1 at 48 h in healthy (p = 0.011), SIRS (p < 0.001), and sepsis (p = 0.006). In conclusion, glutamine at 10 mM, before or after LPS and HS, modulates mHSP90α and lHSP90α in sepsis and SIRS differently and unpredictably. Although it does not alter the stimulation effect on interleukins, glutamine enhances the LPS induction effect on supernatant MCP-1 in all groups. Future research should seek to elucidate better the impact of glutamine and temperature modulation on HSP90α and MCP-1 pathways in sepsis and trauma.


Assuntos
Leucócitos Mononucleares , Sepse , Humanos , Leucócitos Mononucleares/metabolismo , Glutamina/farmacologia , Glutamina/metabolismo , Lipopolissacarídeos/farmacologia , Sepse/metabolismo , Síndrome de Resposta Inflamatória Sistêmica , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucinas/metabolismo , Proteínas de Choque Térmico/metabolismo , RNA Mensageiro/metabolismo
6.
Immunity ; 56(1): 6-8, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630918

RESUMO

Interleukin-22 (IL-22) is a cytokine with pleotropic and opposing roles in physiological and pathological states. In this issue of Immunity, Giannou et al. and Briukhovetska et al. demonstrate how IL-22 is involved in promoting cancer metastasis formation.


Assuntos
Citocinas , Interleucinas
7.
Nutrients ; 15(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36678226

RESUMO

BACKGROUND: Previous studies indicate that dihydromyricetin (DHM) could alleviate intestinal inflammation and improve intestinal barrier integrity, yet the underlying mechanism remains obscure. METHODS: C57BL/6 male mice were fed with a control diet, high-fat diet (HFD), or HFD + DHM diet for 12 weeks. The intestinal permeability and expression of intestinal tight junction (TJ) protein were detected to evaluate the effects of DHM on intestinal barrier integrity. The interleukin 22 (IL-22) production of group 3 innate lymphoid cells (ILC3s) in small intestine lamina propria was tested to clarify the effects of DHM on ILC3s. In addition, an MNK3 cell line, which expresses the same transcription factors and cytokines as ILC3, was used to investigate the molecular mechanism under DHM-induced IL-22 expression. RESULTS: DHM effectively protected HFD-fed mice against intestinal barrier destruction by promoting ILC3 activation and IL-22 secretion, and IL-22 expression increased the expression levels of TJ molecules to protect intestinal barrier integrity. Moreover, DHM increased activation of the AMPK/SIRT3/STAT3 pathway, which in turn promoted IL-22 expression in MNK3 cells. CONCLUSIONS: DHM improved IL-22 production in ILC3 cells to alleviate HFD-induced intestinal barrier destruction via the AMPK/SIRT3/STAT3 pathway.


Assuntos
Sirtuína 3 , Camundongos , Masculino , Animais , Sirtuína 3/genética , Proteínas Quinases Ativadas por AMP , Imunidade Inata , Linfócitos , Camundongos Endogâmicos C57BL , Interleucinas , Transdução de Sinais
8.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674561

RESUMO

Atopic dermatitis (AD) is a common skin disease caused by genetic and environmental factors. However, the mechanisms underlying AD development remain unclear. In this study, we examined the genetic factors contributing to the onset of itch-associated scratching in different strains of mice. Interleukin-31 (IL-31) induces severe scratching and dermatitis in mice. However, the site of action of IL-31 remains unclear. Cutaneous IL-31 and IL-31 receptor A (IL-31RA) mRNAs in the dorsal root ganglion (DRG) are expressed exclusively in the AD model, i.e., NC/Nga mice. Here we evaluated the effects of repeated administration of IL-31 on the scratching behavior in NC/Nga, BALB/c, and C57BL/6 mice. The results showed that repeated administration of IL-31 significantly increased itch-associated scratching (LLS) behavior in the three strains of mice. One hour after an intravenous IL-31 injection, BALB/c mice showed alloknesis-like behavior. Mite infestation and IL-31 administration triggered itchy skin, increased LLS counts and DRG neuronal IL-31RA expression, and eventually caused dermatitis. The dermatitis severity and LLS counts induced by mite infestation and IL-31 administration were in the order NC/Nga > BALB/c > C57BL/6. In conclusion, neuronal IL-31RA expression in the DRG was the most important genetic factor affecting the severity of LLS and dermatitis in mice.


Assuntos
Dermatite Atópica , Infestações por Ácaros , Camundongos , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Gânglios Espinais/metabolismo , Camundongos Endogâmicos C57BL , Prurido/induzido quimicamente , Prurido/genética , Prurido/metabolismo , Pele/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Camundongos Endogâmicos BALB C , Infestações por Ácaros/metabolismo , Modelos Animais de Doenças
9.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674793

RESUMO

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterised by neutrophilic granulocyte (neutrophil)-filled pustules on the palms and soles. The pathogenesis of PPP is poorly understood. This study conducted an identification of the immune mediators associated with PPP and an exploration of apremilast treatment effects on them. We screened for immune mediators elevated in blood taken from 68 patients with PPP versus control participants and included the most promising parameters in the protocol of phase the 2, multicentre study of apremilast (PDE4 inhibitor) in 21 patients with moderate-to-severe PPP (APLANTUS; EudraCT 2016-005122-11) for respective analysis of blood and skin samples of study patients. We investigated stimulated neutrophils and three-dimensional reconstituted epidermis cultures. Interleukin (IL)-19 was found to be the most upregulated immune mediator in the blood of PPP patients. IL-19 serum levels were independent of patients' age, gender, and BMI but were associated with strongly upregulated cutaneous IL-19 expression and correlated with the number of palmoplantar pustules. In patients participating in the APLANTUS study, apremilast reduced pustules more effectively than erythema and scaling. Moreover, this treatment significantly reduced IL-19 blood and skin levels. The reduction in IL-19 blood levels at week 4 correlated with the reduction in pustule counts at week 20 (end of treatment). IL-19 was expressed by neutrophils activated in vitro and induced CXCL6, a neutrophil-attracting chemokine, in epidermis models. This work demonstrates elevated IL-19 levels in the blood and skin of PPP patients and suggests a relevant role of this cytokine in the appearance of pustules in this disorder. It also suggests the suitability of IL-19 blood levels as a predictive biomarker for the treatment response of PPP patients, which should be validated in further studies.


Assuntos
Psoríase , Humanos , Psoríase/metabolismo , Pele/metabolismo , Interleucinas/metabolismo , Talidomida/farmacologia , Talidomida/uso terapêutico
10.
Elife ; 122023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36622106

RESUMO

Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods: Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28. Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels. Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment. Funding: Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).


Hepatitis C is a blood-borne virus that causes thousands of deaths from liver cirrhosis and liver cancer each year. Antiviral therapies can cure most cases of infection in 12 weeks. Unfortunately, treatment is expensive, and sticking with the regimen for 12 weeks can be difficult. It may be especially challenging for unhoused people or those who use injection drugs and who have high rates of hepatitis C infection. Shorter durations of therapy may make it more accessible, especially for high-risk populations. But studies of shorter antiviral treatment durations have yet to produce high enough cure rates. Finding ways to identify patients who would benefit from shorter therapy is a key goal of the World Health Organization. Potential characteristics that may predict a faster treatment response include low virus levels before initiating treatment, patient genetics, drug resistance mutations in the virus, and higher drug levels in the patient's blood during treatment. For example, previous research showed that a rapid decrease in virus levels in a patient's blood two days after starting antiviral therapy with three drugs predicted patient cures after three weeks of treatment. To test if high cure rates could be achieved in just four weeks of treatment, Flower et al. enrolled 52 patients with hepatitis C in a study to receive the most widely accessible dual antiviral treatment (sofosbuvir and daclatasvir). Participants received four or eight weeks of treatment, depending on the amount of viral RNA in their blood after two days of treatment. The results indicate that a rapid decrease in virus levels in the blood does not adequately predict cure rates with four weeks of two-drug combination therapy. However, eight weeks may be highly effective, regardless of viral levels early in treatment. Thirty-four individuals with low virus levels on the second day of treatment received four weeks of therapy, which cured 21 or 62% of them. All seventeen individuals with higher viral levels on day two were cured after eight weeks of treatment. Twelve weeks of retreatment was sufficient to cure the 13 individuals who did not achieve cure with four weeks of therapy. Even patients with drug resistance genes after the first round of therapy responded to a longer second round. Flower et al. show that patient genetics, virus subtype, drug levels in the patient's blood, and viral drug resistance genes before therapy, were not associated with patient cures after four weeks of treatment. Given that retreatment is safe and effective, larger studies are now needed to determine whether eight weeks of therapy with sofosbuvir and daclatasvir may be enough to cure patients with mild liver disease. More studies are also necessary to identify patients that may benefit from shorter therapy durations. Finding ways to shorten antiviral therapy for hepatitis C could help make treatment more accessible and reduce therapy costs for both individuals and governments.


Assuntos
Hepatite C Crônica , Hepatite C , Adulto , Humanos , Sofosbuvir/uso terapêutico , Antivirais , Projetos Piloto , Hepatite C Crônica/tratamento farmacológico , Quimioterapia Combinada , Resultado do Tratamento , Hepacivirus/genética , Genótipo , Ribavirina/uso terapêutico , Interleucinas/genética
11.
Gene ; 854: 147119, 2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36529350

RESUMO

Asthma is a chronic respiratory disease characterized by coughing, wheezing, shortness of breath, chest tightness, overproduction of mucus, and expiratory airflow limitation, which affects >300 million people worldwide. It is triggered by the dynamic interplay of genetic factors and environmental exposure. Th17 cells are an emerging subset of CD4+ T cells, which secrete IL-17A. This proinflammatory cytokine has recently been associated with asthma, autoimmune diseases, and inflammatory disorders. The present case-control study was focused on identifying the involvement of the IL-17A gene in asthma pathogenesis among 150 clinically diagnosed asthma patients and 150 healthy controls (HCs) of South Indian origin. To carry out the study, we aimed to screen the genetic variants of rs2275913G/A and rs8193036C/T and also estimated the serum cytokine levels of the IL-17A cytokine of recruited subjects. Further, we evaluated mRNA expression in selected subjects to correlate with the genetic variants. The results revealed that the mean IL-17A serum levels (161.6 ± 380.1 pg/ml vs. 86.75 ± 90.01 pg/ml) and IgE levels (257.7 ± 133.3 pg/ml vs. 311.2 ± 160.5 pg/ml) in asthma patients were significantly high as compared to healthy controls (p < 0.05). The ROC curves were constructed to compare the cytokine levels of asthma patients and HC, and the area under the curve (AUC) for IL-17A cytokine was 0.64, indicating that the test was satisfactory and significant (95 % CI: 0.575-0.709; p < 0.001). Genotyping of rs2275913G/A polymorphism indicated a 1.6-fold risk (95 % CI-1.02-2.56; p = 0.04) for asthma patients compared to healthy controls, whereas no significant association was observed for rs8193036C/T polymorphism with asthma susceptibility. Under genetic models, GA and AA models showed a protective effect against the disease for rs2275913G/A. In contrast, no statistically significant result was observed among the models of rs8193036C/T when adjusted with age and sex. The mRNA expression levels of the gene were statistically high in patients compared to the HCs, with a 1.8-fold change (p < 0.0001). We conclude that the results indicate IL-17A rs2275913G/A is likely to contribute to protection against the disease, while IL-17A rs8193036C/T shows no association with the disease. However, no correlation was identified in serum cytokine levels concerning genotypes. This comprehensive information in the present study might contribute to developing novel therapeutic strategies for treating inflammatory diseases like asthma. Further studies are warranted to understand the diverse functions of IL-17A concerning its longitudinal stability and its response to clinical interventions with large sample sizes in various ethnicities.


Assuntos
Asma , Interleucina-17 , Humanos , Interleucinas , Suscetibilidade a Doenças , Citocinas , Asma/genética , Asma/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/uso terapêutico , Estudos de Casos e Controles
12.
Cell Immunol ; 383: 104652, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36516653

RESUMO

In this study, we sought to elucidate the roles of the interleukin (IL)-32ß and IL-32γ in mesothelioma cell growth, and vascular endothelial growth factor (VEGF)-A and C-X-C motif chemokine ligand 8 (CXCL8) expression. IL-32 elicited a growth-promoting effect against one of the six mesotheliomas lines and exerted diverse regulatory functions in VEGF-A and CXCL8 secretion from mesotheliomas stimulated with or without IL-17A. Retroviral-mediated transduction of mesothelioma lines with IL-32γ resulted in enhanced IL-32ß expression, which facilitated or suppressed the in vitro growth, and VEGF-A and CXCL8 expression. Overexpressed IL-32ß-augmented growth and VEGF-A and CXCL8 production were mainly mediated through the phosphatidylinositol-3 kinase (PI3K) signaling pathway. On the other hand, overexpressed IL-32ß-deceased growth was mediated through mitogen-activated protein kinase (MAPK) pathway. NCI-H2373IL-32γ tumors grew faster than NCI-H2373Neo tumors in a xenograft model, which was associated with increased vascularity. These findings indicate that IL-32 are involved in the regulation of growth and angiogenic factor production in mesotheliomas.


Assuntos
Mesotelioma Maligno , Mesotelioma , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Isoformas de Proteínas , Mesotelioma/metabolismo
13.
Int Immunopharmacol ; 114: 109525, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36508917

RESUMO

Enhanced angiogenesis is a cancer hallmark and critical for colorectal cancer (CRC) invasion and metastasis. Upon exposure to proangiogenic factors, therefore, targeting tumor-associated proangiogenic factors/receptors hold great promise as a therapeutic modality to treat CRC, particularly metastatic CRC. Accumulating evidence from numerous studies suggests that tumor endothelial cells (ECs) are not only the target of proangiogenic factors, but also function as the cellular source of proangiogenic factors. Studies showed that ECs can produce different proangiogenic factors to participate in the regulation of angiogenesis process, in which ECs-derived interleukins (ILs) show a potential stimulatory effect on angiogenesis via either an direct action on their receptors expressed on progenitor of ECs or an indirect way through enhanced production of other proangiogenic factors. Although a great deal of attention is given to the effects of tumor-derived and immune cell-derived ILs, few studies describe the potential effects of vascular ECs-derived ILs on the tumor angiogenesis process. This review provides an updated summary of available information on proangiogenic ILs, such as IL-1, IL-6, IL-8, IL-17, IL-22, IL-33, IL-34, and IL-37, released by microvascular ECs as potential drivers of the tumor angiogenesis process and discusses their potential as a novel candidate for antiangiogenic target for the treatment of CRC patients.


Assuntos
Neoplasias Colorretais , Células Endoteliais , Humanos , Células Endoteliais/fisiologia , Interleucinas , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Interleucina-8
14.
J Am Heart Assoc ; 12(1): e027222, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36537334

RESUMO

Background Vascular calcification (VC), associated with enhanced cardiovascular morbidity and mortality, is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells. Inflammation promotes VC initiation and progression. Interleukin (IL)-29, a newly discovered member of type III interferon, has recently been implicated in the pathogenesis of autoimmune diseases. Here we evaluated the role of IL-29 in the VC process and underlying inflammatory mechanisms. Methods and Results The mRNA expression of IL-29 was significantly increased and positively associated with an increase in BMP2 (bone morphogenetic protein 2) mRNA level in calcified carotid arteries from patients with coronary artery disease or chronic kidney disease. IL-29 and BMP2 proteins are colocalized in human calcified arteries. IL-29 binding to its specific receptor IL-28Rα (IL-28 receptor α) (IL-29/IL-28Rα) inhibited the proliferation of rat vascular smooth muscle cells without altering cell apoptosis or migration. IL-29 promoted the calcification of rat vascular smooth muscle cells and their osteogenic transdifferentiation in vitro as well as the rat aortic ring calcification ex vivo, induced by the calcification medium or osteogenic medium. The procalcification effect of IL-29 was reduced by pharmacological inhibition of IL-29/IL-28Rα binding as well as suppression of janus kinase 2/signal transducer and activator of transcription pathway activation, accompanied by decreased BMP2 expression in the cultured rat vascular smooth muscle cells. Conclusions These results suggest an important role of IL-29 in VC development, at least partly, via activating the janus kinase 2/signal transducer and activator of transcription 3 signaling. Inhibition of IL-29 or its specific receptor, IL-28Rα, may provide a novel strategy to reduce VC in patients with vascular diseases.


Assuntos
Proteína Morfogenética Óssea 2 , Calcificação Vascular , Humanos , Ratos , Animais , Proteína Morfogenética Óssea 2/genética , Janus Quinase 2/efeitos adversos , Janus Quinase 2/metabolismo , Citocinas/metabolismo , Calcificação Vascular/patologia , Células Cultivadas , RNA Mensageiro/metabolismo , Interleucinas/farmacologia , Miócitos de Músculo Liso/metabolismo , Fator de Transcrição STAT3/metabolismo
15.
J Clin Lab Anal ; 37(1): e24799, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36478612

RESUMO

BACKGROUND: Numerous studies have described the critical importance of interleukin (IL) -36γ in host defense against lung infections, but it is unknown whether it plays a role in infectious pleural effusion (IPE). This study aimed to examine the levels of IL-36γ in pleural effusions of different etiologies and evaluate the diagnostic accuracy of IL-36γ in the differential diagnosis of IPE. METHODS: A total of 112 individuals was enrolled in this research. IL-36γ levels in pleural fluids of all 112 patients were measured by enzyme-linked immunosorbent assay (ELISA). We also characterized these markers' diagnostic values across various groups. RESULTS: Patients with tuberculous pleural effusion (TPE) and parapneumonic effusion (PPE) had exhibited markedly higher IL-36γ levels in their pleural fluid than the malignant pleural effusion (MPE) and transudative effusion patients. Furthermore, the IL-36γ concentrations in TPE patients were evidently higher than in uncomplicated parapneumonic effusion (UPPE) patients but significantly lower than in complicated parapneumonic effusion (CPPE)/empyema patients. Pleural fluid IL-36γ is a useful marker to differentiate TPE from UPPE, at a cut-off value for 657.5 pg/ml (area under the curve = 0.904, p < 0.0001) with 70.0% sensitivity and 95.7% specificity. CONCLUSIONS: The elevated IL-36γ in pleural effusion may be used as a novel biomarker for infectious pleural effusion diagnosis, particularly in patients with CPPE/empyema, and is a potentially promising biomarker to differentiate between TPE and UPPE.


Assuntos
Derrame Pleural Maligno , Derrame Pleural , Pneumonia , Humanos , Derrame Pleural/diagnóstico , Derrame Pleural/patologia , Biomarcadores/análise , Derrame Pleural Maligno/diagnóstico , Pneumonia/diagnóstico , Interleucinas , Diagnóstico Diferencial
16.
Cytokine ; 162: 156117, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36586188

RESUMO

The current study examined five cytokines, three belong to interleukin (IL)-1 family (IL-36α, IL-37 and IL-38), one belongs to IL-12 family (IL-39) and one has not been assigned to a family (IL-40), in the serum of 110 male patients with ankylosing spondylitis (AS) and 103 male controls. Studies regarding these cytokines in AS are very limited. Therefore, the significance of IL-36α, IL-37, IL-38, IL-39 and IL-40 as biomarkers of AS was evaluated. Cytokine levels were measured using enzyme-linked immunosorbent assay kits. Results revealed that serum levels (median and interquartile range) of IL-36α (90.7; 53.7-166.2 vs 39.7; 31.3-59.2 pg/mL; probability [p] < 0.001), IL-37 (161.3; 62.8-236.6 vs 58.4; 46.8-80.7 ng/mL; p < 0.001), IL-38 (135.8; 78.2-213.5 vs 65.8; 51.1-87.1 pg/mL; p < 0.001), IL-39 (57.7; 34.1-92.3 vs 29.1; 19.3-58.6 ng/L; p < 0.001) and IL-40 (3.89; 2.99-6.19 vs 2.10; 1.75-2.68 ng/L; p < 0.001) were significantly higher in AS patients than in controls. Besides, they were of value in distinguishing between AS patients and controls as evidenced by the receiver operating characteristic curve analysis: area under the curve = 0.797 (IL-36α), 0.75 (IL-37), 0.797 (IL-38), 0.728 (IL-39) and 0.886 (IL-40). Some of these cytokines were significantly correlated, but no correlation with AS activity was found. In conclusion, the levels of IL-36α, IL-37, IL-38, IL-39 and IL-40 were up-regulated in the serum of AS patients regardless of age, age at disease onset, disease duration, disease activity or HLA-B27.


Assuntos
Espondilite Anquilosante , Humanos , Masculino , Interleucinas , Interleucina-1 , Citocinas , Biomarcadores
17.
Biochem Biophys Res Commun ; 642: 145-153, 2023 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-36577251

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis and a lack of specific targets and targeted therapeutics. Previously, we have reported that COL8A1, which is highly expressed in the mesenchymal stem-like (MSL) subtype of TNBC, facilitates TNBC growth via FAK/Src activation. Furthermore, we have found that COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. However, the mechanism of invasion and metastasis by COL8A1 remains unclear. Here, we investigated the biological function of COL8A1 on the invasion and metastasis of MDA-MB-231 cells. METHODS: The invasion and metastasis of MDA-MB-231 cells were evaluated using three-dimensional (3D) culture methods and xenograft mouse models. DNA microarray analysis examined the gene expression in COL8A1-overexpressing MDA-MB-231 cells and control cells. Gene expression was verified using RT-qPCR. RESULTS: COL8A1-deficient cells showed little or no metastasis, whereas forced expression of COL8A1 in MDA-MB-231 cells, the MSL subtype of TNBC cell lines, significantly promoted distant metastasis after tumor resection. As with in vivo, 3D invasion assay revealed that COL8A1 increased the invasion capacity of MDA-MB-231 and Hs578T cells, classified into the MSL subtype of TNBC. DNA microarray analysis for COL8A1-overexpressing cells indicated that COL8A1 induces interleukin 1B (IL1B) and matrix metalloproteinase-1 (MMP1) expression, both of which are correlated with COL8A1 expression in the mesenchymal subtypes of TNBC, and the Kaplan-Meier plotter provided evidence that the prognosis in the MSL subtype was strongly associated with both gene expressions and COL8A1 expression. Pharmacological inhibitor treatment showed that COL8A1 regulated IL1B and MMP1 expression through a different pathway. Moreover, the knockdown of each gene expression reduced the invasion capacity of COL8A1-overexpressing MDA-MB-231 and Hs578T cells. CONCLUSION: Our findings indicate that COL8A1-induced IL1B and MMP1 enhanced the invasion and metastasis of the MSL subtype of TNBC. Considering our previous findings that COL8A1 promotes tumor growth, COL8A1 may be a prognostic and practical therapeutic target in TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Metaloproteinase 1 da Matriz , Neoplasias de Mama Triplo Negativas/patologia , Modelos Animais de Doenças , Interleucinas , DNA , Proliferação de Células , Movimento Celular/genética , Interleucina-1beta
18.
J Dermatol ; 49(1): 124-132, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34611926

RESUMO

Mamushi bites cause swelling and pain that extend from the bitten site. The coagulopathic, anti-coagulopathic, and vasculopathic actions of mamushi venom result in various laboratory abnormalities, occasionally with muscular, renal, and other organ damage. We investigated the serum biomarkers that were associated with the pathogenesis of mamushi bites, focusing on markers related to tissue-damage and neutrophil activation. Twenty patients (one case of grade 2, 13 cases of grade 3, and six cases of grade 4 of severity) seen by us in one summer season were enrolled. Peripheral blood samples were taken from the patients on day 0, day 2, and day 7 after mamushi bites. In addition to routine blood examination, serum samples were subjected to enzyme-linked immunosorbent assay for citrullinated histone H3 (CitH3), interleukin (IL)-8, IL-17A, IL-22, vascular endothelial growth factor (VEGF), high mobility group box protein 1 (HMGB1), tumor necrosis factor (TNF)-α, and IL-33. Creatinine kinase (CK) values significantly correlated with prothrombin time (PT) levels, suggesting that muscular damage is associated with exaggerated coagulation and fibrinolysis. In the vast majority of patients, HMGB1, TNF-α, and IL-33 were under detection levels. Neutrophil counts did not correlate with PT or CK, indicating that the coagulation disorder and muscular damage were virtually independent of the neutrophil activation. The neutrophil number significantly correlated with CitH3, a representative marker of neutrophil extracellular traps. Moreover, there were significant correlations between neutrophil number, CitH3, IL-8, IL-22, and VEGF. Our study suggests that there are two major cascades in mamushi bites. One is an already characterized venom effect on coagulation, vessels, and muscles. In the other novel cascade, we propose that neutrophil activation with IL-8 leads to the production of IL-22 and VEGF. This sequential event may contribute to both vascular damage and repair.


Assuntos
Armadilhas Extracelulares , Fator A de Crescimento do Endotélio Vascular , Animais , Humanos , Interleucina-8 , Interleucinas , Serpentes
19.
Dis Markers ; 2022: 5946290, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505098

RESUMO

Background: Dilated cardiomyopathy is a primary myocardial disease and one of the critical causes of heart failure. It is the most common indication for heart transplantation worldwide, and most idiopathic dilated cardiomyopathies are sporadic and multifactorial. Evidence has supported that several inflammatory cytokines and immune responses are involved in its pathological process. Interleukin-32 is a proinflammatory cytokine and is elevated during the worsening cardiac function. Herein, we evaluated the correlation between interleukin-32 gene polymorphisms (rs12934561 and rs28372698) and the susceptibility to dilated cardiomyopathy. Methods: We enrolled 418 dilated cardiomyopathy patients and 437 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping the two single-nucleotide polymorphisms (SNPs), and SPSS software was used for statistical analyses. Results: The C allele and CC genotype frequencies of rs12934561 were remarkably elevated in dilated cardiomyopathy patients compared to controls (both P < 0.001). The A allele and AA genotype frequencies of rs28372698 significantly decreased in dilated cardiomyopathy patients (P = 0.004 and P = 0.02, respectively). Compared to TT/TC genotype carriers of rs12934561, CC homozygotes presented an increased risk of dilated cardiomyopathy when the left ventricular ejection fraction no more than 30% (P = 0.02). Conclusions: The IL-32 gene polymorphisms might implicate in DCM risk in the Chinese Han population, and rs12934561 could be a potential forecasting factor for screening high-risk population for DCM.


Assuntos
Cardiomiopatia Dilatada , Humanos , Cardiomiopatia Dilatada/genética , Citocinas , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Volume Sistólico , Função Ventricular Esquerda
20.
Ital J Pediatr ; 48(1): 201, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36539847

RESUMO

BACKGROUND: Urticarial lesions develop as a result of the activation of mast cells which, through the release of mediators, influence the formation of local inflammatory infiltrates. Changes in the expression of many cytokines and chemokines are observed in the course of urticaria. The aim of the study was to evaluate serum levels of interleukin (IL)-6, IL-17A, IL-18, IL-23, regulated on activation, normal T cell expressed and secreted (RANTES) and interferon (IFN)-γ-inducible protein-10 (IP-10) in children with acute urticaria and exacerbation of chronic urticaria in comparison to healthy volunteers. Moreover, we made an attempt to identify factors associated with the acute phase of urticaria and factors predicting the course of the disease among the studied parameters. METHODS: We retrospectively analyzed 32 children with acute urticaria and 32 children with chronic urticaria. The control group consisted of 40 healthy children. Each patient was clinically evaluated. Serum concentrations of selected cytokines and chemokines were determined by using enzyme-linked immunosorbent assay. RESULTS: Patients with acute and chronic urticaria had higher concentrations of IL-6 and IL-17A (p < 0.001) and lower concentrations of IL-18, IL-23, RANTES and IP-10 (p < 0.001) as compared to the control group. A significant association between IL-6 and IP-10 with the acute phase of urticaria has been demonstrated. There was no correlation of the studied cytokines and chemokines with disease activity. CONCLUSIONS: In children with acute phase of urticaria, the cytokine serum concentration differs compared to healthy subjects. IL-6 and IP-10 seem to be useful in differentiating children with acute phase of urticaria and healthy ones. The search for factors predicting the course of the disease requires further studies.


Assuntos
Urticária Crônica , Urticária , Humanos , Criança , Interleucina-18 , Interleucina-6 , Quimiocina CXCL10 , Interleucina-17 , Interleucina-23 , Estudos Retrospectivos , Linfócitos T/metabolismo , Quimiocinas/metabolismo , Interleucinas , Citocinas , Urticária/diagnóstico
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