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BACKGROUND: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. METHODS: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. RESULTS: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (ß±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. CONCLUSIONS: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.
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Biomarcadores , Inflamación , Interleucina-18 , Accidente Cerebrovascular , Humanos , Masculino , Femenino , Biomarcadores/sangre , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/diagnóstico por imagen , Persona de Mediana Edad , Interleucina-18/sangre , Anciano , Inflamación/sangre , Estudios de Cohortes , Incidencia , Factores de Riesgo , Imagen por Resonancia Magnética , Disfunción Cognitiva/sangre , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/diagnóstico por imagenRESUMEN
OBJECTIVE: Recently, the Pediatric Rheumatology International Trials Organization (PRINTO) has proposed revisions to the current International League of Associations for Rheumatology (ILAR) criteria for systemic juvenile idiopathic arthritis (s-JIA). Interleukin (IL)-18 overproduction plays a significant role in the pathogenesis of s-JIA. This study aimed to evaluate the performance of the PRINTO criteria compared with the ILAR criteria and determine whether serum IL-18 levels improve their diagnostic performances. METHODS: Overall, 90 patients with s-JIA and 27 patients with other febrile disease controls presenting with a prolonged fever of > 14 days and arthritis and/or erythematous rash were enrolled. The ILAR and PRINTO classification criteria were applied to all patients and examined with expert diagnoses. Enzyme-linked immunosorbent assay was used for measuring serum IL-18 levels. RESULTS: The PRINTO criteria had higher sensitivity but lower specificity than the ILAR criteria (sensitivity: PRINTO 0.856, ILAR 0.533; specificity: PRINTO 0.259, ILAR 0.851). With the addition of serum IL-18 levels ≥ 4,800 pg/mL, the sensitivity of the ILAR criteria and specificity of the PRINTO criteria were improved to 1.000 and 1.000, respectively. PRINTO plus serum IL-18 levels ≥ 4,800 pg/mL showed the highest value in Youden's index (sensitivity - [1 - specificity]). CONCLUSION: Serum IL-18 levels could improve the diagnostic performance of the PRINTO and ILAR criteria for s-JIA. The PRINTO criteria plus serum IL-18 levels ≥ 4,800 pg/mL could be the best diagnostic performance for s-JIA.
RESUMEN
BACKGROUND: Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections. METHODS: Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined. RESULTS: In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations. CONCLUSIONS: Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.
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Monocitos , Streptococcus pyogenes , Humanos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Caspasa 8 , Citocinas/genética , Interleucina-18/genética , Interleucina-8 , Monocitos/metabolismo , Streptococcus pyogenes/genéticaRESUMEN
The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.
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Adenocarcinoma/secundario , Proteínas Portadoras/fisiología , Neoplasias Colorrectales/patología , Inflamasomas/fisiología , Células Asesinas Naturales/inmunología , Neoplasias Hepáticas/secundario , Adenocarcinoma/inmunología , Animales , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas de Unión al Calcio/deficiencia , Caspasa 1/deficiencia , Línea Celular Tumoral , Neoplasias Colorrectales/inmunología , Citotoxicidad Inmunológica , Proteínas de Unión al ADN/deficiencia , Proteína Ligando Fas/fisiología , Microbioma Gastrointestinal , Inmunidad Innata , Vigilancia Inmunológica , Inflamasomas/deficiencia , Interleucina-18/fisiología , Interleucina-1beta/fisiología , Neoplasias Hepáticas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/fisiología , Quimera por Radiación , Tolerancia a Radiación , Microambiente TumoralRESUMEN
OBJECTIVE: Interleukin-18 (IL-18) is a proinflammatory cytokine. This study aims to determine whether there is a causal relationship between circulating IL-18 concentrations and the risk of inflammatory and autoimmune diseases. METHODS: We collected significant single nucleotide polymorphisms (SNPs) associated with circulating IL-18 levels (p < 5 × 10-8) as instrumental variables (IVs) from a genome-wide association study (GWAS) involving 21,758 individuals of European descent. We mainly employed the inverse-variance weighed (IVW) method of two-sample Mendelian randomization (TSMR) analysis to estimate the causality of circulating IL-18 levels on inflammatory and autoimmune diseases. RESULTS: The IVW method results showed evidence of a causal relationship between IL-18 and the risk of systemic lupus erythematosus (SLE) (OR = 1.32; 95% CI 1.15, 1.50; p < .001) and type 1 diabetes (T1D) (OR = 1.22; 95% CI 1.06, 1.42; p = .007) in individuals of European ancestry. No significant heterogeneity or horizontal pleiotropy for SLE and T1D was detected. The sensitivity analysis, which involved removing confounding SNP, produced similar results for SLE and T1D. The results of sensitivity analysis using leave-one-out method indicated no single SNP significantly influenced the analysis results. However, we did not find any significant findings for multiple sclerosis, psoriasis, asthma, and osteoarthritis. CONCLUSIONS: Our analyses suggest that circulating IL-18 is significantly related to SLE and T1D and may serve as a potential target for the treatment of these diseases.
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Enfermedades Autoinmunes , Diabetes Mellitus Tipo 1 , Lupus Eritematoso Sistémico , Humanos , Diabetes Mellitus Tipo 1/genética , Estudio de Asociación del Genoma Completo , Interleucina-18/genética , Lupus Eritematoso Sistémico/genéticaRESUMEN
Chronic pain has been proven to be an independent disease, other than an accompanying symptom of certain diseases. Interleukin-18 (IL-18), a pro-inflammatory cytokine with pleiotropic biological effects, participates in immune modulation, inflammatory response, tumor growth, as well as the process of chronic pain. Compelling evidence suggests that IL-18 is upregulated in the occurrence of chronic pain. Antagonism or inhibition of IL-18 expression can alleviate the occurrence and development of chronic pain. And IL-18 is located in microglia, while IL-18R is mostly located in astrocytes in the spinal cord. This indicates that the interaction between microglia and astrocytes mediated by the IL-18/IL-18R axis is involved in the occurrence of chronic pain. In this review, we described the role and mechanism of IL-18 in different types of chronic pain. This review provides strong evidence that IL-18 is a potential therapeutic target in pain management.
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Dolor Crónico , Interleucina-18 , Humanos , Interleucina-18/metabolismo , Interleucina-18/farmacología , Dolor Crónico/metabolismo , Citocinas/metabolismo , Microglía , AstrocitosRESUMEN
BACKGROUND: Numerous biological interventions and small molecules are used to treat Crohn's disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn's disease. AIMS: The aim of this study was to elucidate the expression of precursor and mature IL-18 in patients with Crohn's disease who exhibited varied responses to cytokine-targeted treatments and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. METHODS: We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expression of precursor and mature IL-18 was analyzed in patients with Crohn's disease. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in an acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. RESULTS: Precursor and mature IL-18 expression was upregulated and goblet cell function was impaired in patients with Crohn's disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. CONCLUSIONS: The newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn's disease.
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Anticuerpos Monoclonales , Enfermedad de Crohn , Células Caliciformes , Interleucina-18 , Interleucina-18/metabolismo , Interleucina-18/inmunología , Animales , Células Caliciformes/inmunología , Células Caliciformes/patología , Células Caliciformes/efectos de los fármacos , Humanos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Ratones , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Masculino , Modelos Animales de Enfermedad , Colitis/inmunología , Colitis/tratamiento farmacológico , Adulto , Ratones Endogámicos C57BLRESUMEN
The cytokine storm syndrome (CSS) associated with systemic juvenile idiopathic arthritis (sJIA) has widely been referred to as macrophage activation syndrome (MAS). In this chapter, we use the term sJIA-associated CSS (sJIA-CSS) when referring to this syndrome and use the term MAS when referencing publications that specifically report on sJIA-associated MAS.
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Artritis Juvenil , Síndrome de Liberación de Citoquinas , Humanos , Artritis Juvenil/complicaciones , Artritis Juvenil/inmunología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Citocinas/metabolismo , NiñoRESUMEN
A vast body of evidence provides support to a central role of exaggerated production of interferon-γ (IFN-γ) in causing hypercytokinemia and signs and symptoms of hemophagocytic lymphohistiocytosis (HLH). In this chapter, we will describe briefly the roles of IFN-γ in innate and adaptive immunity and in host defense, summarize results from animal models of primary HLH and secondary HLH with particular emphasis on targeted therapeutic approaches, review data on biomarkers associated with activation of the IFN-γ pathway, and discuss initial efficacy and safety results of IFN-γ neutralization in humans.
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Síndrome de Liberación de Citoquinas , Inmunidad Innata , Interferón gamma , Linfohistiocitosis Hemofagocítica , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Interferón gamma/inmunología , Animales , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Inmunidad Innata/efectos de los fármacos , Inmunidad Adaptativa/efectos de los fármacosRESUMEN
Interleukin-1 is a prototypic proinflammatory cytokine that is elevated in cytokine storm syndromes (CSSs), such as secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS). IL-1 has many pleotropic and redundant roles in both innate and adaptive immune responses. Blockade of IL-1 with recombinant human interleukin-1 receptor antagonist has shown efficacy in treating CSS. Recently, an IL-1 family member, IL-18, has been demonstrated to be contributory to CSS in autoinflammatory conditions, such as in inflammasomopathies (e.g., NLRC4 mutations). Anecdotally, recombinant IL-18 binding protein can be of benefit in treating IL-18-driven CSS. Lastly, another IL-1 family member, IL-33, has been postulated to contribute to CSS in an animal model of disease. Targeting of IL-1 and related cytokines holds promise in treating a variety of CSS.
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Síndrome de Liberación de Citoquinas , Interleucina-1 , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Interleucina-1/antagonistas & inhibidores , Interleucina-1/inmunología , Interleucina-1/genética , Interleucina-1/metabolismo , Animales , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteínas de Unión al Calcio/genética , Interleucina-18/genética , Interleucina-18/inmunología , Síndrome de Activación Macrofágica/inmunología , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Proteínas Adaptadoras de Señalización CARDRESUMEN
OBJECTIVE: We assessed the levels of Interleukin-10 (IL-10), Interleukin-12 (IL-12), and Interleukin-18 (IL-18) in the gingival crevicular fluid (GCF) of subjects with advanced periodontitis (SIII-SIV) compared to healthy controls and evaluated their correlations with clinical measurements. METHODS: This cross-sectional study involved subjects (n = 60) diagnosed with stage III grade B-C (n = 13) to stage IV grade C (n = 17) periodontitis, and periodontally healthy controls (n = 30). Clinical periodontal measurements involved full-mouth. The concentrations of IL-10, IL-12, and IL-18 were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were no significant differences in IL-12 level and IL-18/IL-10 ratio between the healthy and periodontitis groups (p = 0.413, p = 0.636, respectively). The IL-10 and IL-18 levels were significantly higher in the periodontitis group than in controls (p < 0.001, p < 0.001, respectively). Significant associations were observed between the periodontitis and IL-10 and IL-18 levels (OR = 1.46, %95 CI 1.19-1.795; OR = 1.13, %95 CI 1.059-1.207, respectively) (p < 0.001, p < 0.001, respectively). CONCLUSIONS: There was a correlation between pocket depth and the presence of IL-18 and a strong association between periodontitis and a high level of IL-18. However, there were no direct correlations among the three biomarkers and IL-18/IL-10 ratio, indicating that their roles in periodontal health are complex and multidimensional. CLINICAL RELEVANCE: Understanding the cytokine dynamics in GCF provides valuable insights into their potential clinical implications for periodontal disease diagnosis, risk assessment, and tailored therapeutic interventions.
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Ensayo de Inmunoadsorción Enzimática , Líquido del Surco Gingival , Interleucina-10 , Interleucina-18 , Humanos , Estudios Transversales , Masculino , Femenino , Líquido del Surco Gingival/química , Interleucina-10/metabolismo , Interleucina-18/metabolismo , Persona de Mediana Edad , Adulto , Interleucina-12/metabolismo , Estudios de Casos y Controles , Índice Periodontal , Periodontitis , BiomarcadoresRESUMEN
High dietary phosphorus intake (P-In) and high acid loads may adversely affect kidney function. In animal models, excessive phosphorus intake causes renal injury, which, in humans, is also inducible by chronic metabolic acidosis. We thus examined whether habitually high P-In and endogenous acid production during childhood and adolescence may be early indicators of incipient renal inflammatory processes later in adulthood. P-In and acid-base status were longitudinally and exclusively determined by biomarker-based assessment in 277 healthy children, utilizing phosphate and net acid excretion (NAE) measurements in 24 h urine samples repeatedly collected between the ages of 3 and 17 years. Standard deviation scores (by sex and age) were calculated for anthropometric data and for the urinary biomarkers available within age range 3-17 years. Multivariable linear regression was used to analyze the relations of phosphate excretion and NAE with the adulthood outcome circulating interleukin-18 (IL-18), a marker of inflammation and kidney dysfunction. After adjusting for growth- and adulthood-related covariates and pro-inflammatory biomarkers to rule out confounding by non-renal inflammatory processes, regression models revealed a significant positive relationship of long-term NAE (p = 0.01), but not of long-term phosphate excretion with adult serum IL-18. Similar significant positive regression results were obtained after replacing NAE with 24 h urinary ammonium excretion as the exposition variable. Our results suggest that even moderate elevations in renal ammonia production, as caused by habitually higher acid loading during growth, may affect the intrarenal pro-inflammatory system in the long-term, known to be boosted by acidosis-induced raised ammoniagenesis.
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Acidosis , Interleucina-18 , Riñón , Adolescente , Adulto , Animales , Niño , Preescolar , Humanos , Acidosis/metabolismo , Biomarcadores/metabolismo , Interleucina-18/metabolismo , Riñón/metabolismo , Fosfatos/metabolismoRESUMEN
The inflammasome regulates the innate inflammatory response and is involved in autoimmune diseases. In this study, we explored the levels of IL-18 and IL-1ß in serum and urine and the influence of various single-nucleotide polymorphisms (SNPs) on kidney lesions at diagnosis in patients with ANCA-associated vasculitis (AAV) and their clinical outcomes. Ninety-two patients with renal AAV were recruited, and blood and urine were collected at diagnosis. Serum and urine cytokine levels were measured by ELISA. DNA was extracted and genotyped using TaqMan assays for SNPs in several inflammasome genes. Lower serum IL-18 (p = 0.049) and the IL-18 rs187238 G-carrier genotype (p = 0.042) were associated with severe fibrosis. The IL-18 rs1946518 TT genotype was associated with an increased risk of relapse (p = 0.05), whereas GG was related to better renal outcomes (p = 0.031). The rs187238 GG genotype was identified as a risk factor for mortality within the first year after AAV diagnosis, independent of the requirement for dialysis or lung involvement (p = 0.013). We suggest that decreased cytokine levels could be a surrogate marker of scarring and chronicity of the renal lesions, together with the rs187238 GG genotype. If our results are validated, the rs1946518 TT genotype predicts the risk of relapse and renal outcomes during follow-up.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Inflamasomas , Interleucina-18 , Interleucina-1beta , Polimorfismo de Nucleótido Simple , Humanos , Interleucina-18/genética , Interleucina-18/sangre , Masculino , Femenino , Inflamasomas/genética , Persona de Mediana Edad , Interleucina-1beta/genética , Interleucina-1beta/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Anciano , Riñón/patología , Riñón/metabolismo , Genotipo , Adulto , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
Cisplatin is still a widely used anticancer drug characterized by significant nephrotoxicity. Acute kidney injury (AKI), diagnosed based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, has limitations, including a delayed increase in creatinine. We determined the usefulness of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in diagnosing AKI according to the KDIGO criteria in patients treated with cisplatin. We recruited 21 subjects starting cisplatin-based chemotherapy (Cisplatin-based group) and 11 treated with carboplatin-based chemotherapy or 5-fluorouracil regimens (non-cisplatin-based group). Blood and urine samples were collected during four subsequent cycles of chemotherapy (68 and 38 cycles, respectively). AKI occurred in four patients in the cisplatin-based group (5.9% of 68 cisplatin-based chemotherapy cycles). Among them, three urinary markers were increased by over 100% in two cases, two in one case and one in another. A doubling of at least one investigated parameter was observed more frequently during cisplatin-based chemotherapy (80.3% vs. 52.8%; OR = 3.65, 95% CI: 1.49-8.90; p < 0.01). The doubling of at least one new urinary AKI marker was more common in patients receiving cisplatin and frequently was not associated with overt AKI. Thus, a subclinical kidney injury detected by these markers occurs more frequently than deterioration in kidney function stated with creatinine changes.
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Lesión Renal Aguda , Cisplatino , Humanos , Cisplatino/efectos adversos , Lipocalina 2 , Creatinina , Interleucina-18 , Riñón , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/diagnósticoRESUMEN
OBJECTIVE: To explore the correlations between serum levels of brain-derived neurotrophic factor (BDNF), interleukin-18 (IL-18) and hypersensitivity C-reactive protein (hs-CRP) in patients with acute cerebral infarction and vascular cognitive impairment (VCI), and to provide some clinical bases for early prevention of VCI. METHODS: A total of 160 patients with acute cerebral infarction admitted in Department of Neurology of Jincheng People' s Hospital from May 2019 to April 2020 were enrolled in this study and were devided into three groups according to whether or not combined with cognitive impairment, including no cognitive impairment group (NCI, 57 cases), vascular cognitive impairment no dementia group (VCIND, 56 cases) and vascular dementia group (VaD, 47 cases). The cognitive function of all the patients were evaluated by Montreal cognitive assessment (MoCA). The National Institute of Health stroke scale (NIHSS) was used to assess the degree of neurological deficit (mild-, moderate-, severe-neurologic deficit group). The infarct size was calculated by Pullicino' s method (small-, middle-, large-infarct group). The levels of serum BDNF and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA), and serum levels of hs-CRP were measured by immunoturbidimetry during the acute phase (0-7 d), recovery period (15-30 d) and 6 months after cerebral infarction. The effects of varying degrees of neurological deficits and different size of infarction on BDNF, IL-18 and hs-CRP were observed. The levels of serum BDNF, IL-18 and hs-CRP in the patients of the three groups with acute, convalescent and six-month cerebral infarction were compared, and their correlations with VCI were analyzed. RESULTS: Serum BDNF level and MoCA scores in mild-neurologic deficit group and small-infarct group were significantly higher than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). Their levels of IL-18 and hs-CRP were significantly lower than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). The levels of serum BDNF in NCI group, VCIND group and VaD group during the acute phase, convalescence and 6 months after cerebral infarction were in a significant decline, and the differences during the acute phase and recovery period were statistically significant (P < 0.05). The levels of IL-18 and hs-CRP during the acute phase, recovery period and 6 months after cerebral infarction showed a significant increasing trend with significance (P < 0.05). Correlation analysis revealed that the levels of BDNF was positively correlated with MoCA scores but negatively correlated with the severity of cognitive impairment while the expression levels of IL-18 and hs-CRP were negatively correlated with MoCA scores but positively correlated with the severity of cognitive impairment. CONCLUSION: Serum BDNF, IL-18 and hs-CRP are involved in the pathological process of occurrence and development of VCI in the patients with acute cerebral infarction. BDNF has a protective effect on VCI while IL-18 and hs-CRP cause severe cognitive impairment. The levels of serum BDNFãIL-18 and hs-CRP in the patients with acute ischemic cerebral infarction are closely related to the severity of cognitive impairment and can be used as biomarkers of early diagnosis of VCI.
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Factor Neurotrófico Derivado del Encéfalo , Proteína C-Reactiva , Infarto Cerebral , Disfunción Cognitiva , Interleucina-18 , Humanos , Factor Neurotrófico Derivado del Encéfalo/sangre , Interleucina-18/sangre , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Infarto Cerebral/sangre , Masculino , Femenino , Disfunción Cognitiva/sangre , Disfunción Cognitiva/etiología , Anciano , Demencia Vascular/sangre , Persona de Mediana Edad , Pruebas de Estado Mental y DemenciaRESUMEN
OBJECTIVES: The interleukin (IL)-18 signalling pathway is involved in animal models of collagen-induced arthritis, but the role of this pathway in autoantibody-induced arthritis is poorly understood. An autoantibody-induced arthritis model, K/BxN serum transfer arthritis, reflects the effector phase of arthritis and is important in innate immunity including neutrophils and mast cells. This study aimed to investigate the role of the IL-18 signalling pathway in autoantibody-induced arthritis using IL-18 receptor (IL-18R) α-deficient mice. METHODS: K/BxN serum transfer arthritis was induced in IL-18Rα-/- and wild-type B6 (controls) mice. The severity of arthritis was graded, and histological and immunohistochemical examinations were performed on paraffin-embedded ankle sections. Total Ribonucleic acid (RNA) isolated from mouse ankle joints was analysed by real-time reverse transcriptase-polymerase chain reaction. RESULTS: IL-18 Rα-/- mice had significantly lower arthritis clinical scores, neutrophil infiltration, and numbers of activated, degranulated mast cells in the arthritic synovium than in controls. IL-1ß, which is indispensable for the progression of arthritis, was significantly downregulated in inflamed ankle tissue in IL-18 Rα-/- mice. CONCLUSIONS: IL-18/IL-18Rα signalling contributes to the development of autoantibody-induced arthritis by enhancing synovial tissue expression of IL-1ß and inducing neutrophil recruitment and mast cell activation. Therefore, inhibition of the IL-18Rα signalling pathway might be a new therapeutic strategy for rheumatoid arthritis.
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Artritis Experimental , Artritis Reumatoide , Animales , Ratones , Autoanticuerpos , Interleucina-18 , Mastocitos/patología , Infiltración Neutrófila , Receptores de Interleucina-18/metabolismo , Ratones Noqueados , Artritis Experimental/metabolismoRESUMEN
Background and Objectives: Systemic inflammatory response syndrome (SIRS) is one of the most significant complications after on-pump heart surgery procedures. High cytokine levels have been shown after open-heart surgeries and a genetic predisposition seems to be an important underlying modulatory characteristic for SIRS. To investigate the association between interleukin 18 -607 C/A, interleukin 18 -137 G/C and osteopontin 9250 C/T genetic polymorphisms and SIRS in on-pump CABG patients. Materials and Methods: Two hundred consecutive elective on-pump CABG patients were recruited prospectively to the study. Genomic DNA was extracted from whole blood and genotyping was determined by sequence specific PCR or PCR-RFLP methods for related polymorphisms. Results: SIRS incidence was 60.2%, 38.1%, 18.9% on postoperative day 1, 2 and 3, respectively, in the whole study population. The SIRS rate on the second postoperative day was 13% and 43.4%, respectively, in osteopontin 9250 C/T T allele non-carriers and carriers (p = 0.004). WBC (White Blood Cell) counts were higher on day 2 and 3 in osteopontin 9250 C/T T allele carriers compared to non-carriers (day 2; 12.7 ± 4 vs. 10.5 ± 2.4 (p = 0.015), day 3; 11.8 ± 4 vs. 9.1 ± 4.7 (p = 0.035)). The average ICU stay was 3.1 ± 7.4, 1.28 ± 0.97 for IL 18-137 G/C C allele carriers and non-carriers, respectively (p = 0.003), and in the IL 18-137 G/C C allele carriers, SIRS developed in 42.2% by the second postoperative day whereas the rate was 57.8% in non-carriers (p = 0.025). Conclusions: The current research revealed a possible link between osteopontin 9250 C/T and IL18-137 G/C genetic polymorphism and SIRS and morbidity in on-pump CABG patients.
Asunto(s)
Puente de Arteria Coronaria , Interleucina-18 , Osteopontina , Síndrome de Respuesta Inflamatoria Sistémica , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Puente de Arteria Coronaria/efectos adversos , Predisposición Genética a la Enfermedad , Genotipo , Interleucina-18/sangre , Interleucina-18/genética , Interleucina-18/inmunología , Osteopontina/sangre , Osteopontina/genética , Osteopontina/inmunología , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Estudios Prospectivos , Síndrome de Respuesta Inflamatoria Sistémica/genética , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/etiologíaRESUMEN
In 89 patients with COVID-19, the ratios between IL-18, free IL-18, and IL-18-binding protein (IL-18BP) were analyzed depending on severity and outcome of the disease. At admission to the hospital, the levels of IL-18 and free IL-18 were significantly higher than 3 months after discharge from the hospital, the levels IL-18BP of being almost the same. In patients with more severe lung injury (computed tomography data), the levels of IL-18 and free IL-18 were higher and IL-18BP levels were lower than in patients with mild and moderate COVID-19. Three months after discharge from the hospital, no differences between these parameters were found. In 9 patients who died in the hospital, free IL-18 levels were significantly higher and IL-18BP levels were lower than in survivors. Thus, high levels of bioactive free IL-18 in combination with low levels of IL-18BP can be indicative of severe inflammatory phase of COVID-19 and the risk of worse clinical outcomes.
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COVID-19 , Interleucina-18 , Humanos , Interleucina-18/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Proteínas Portadoras , Interleucina-1beta/metabolismoRESUMEN
Systemic juvenile idiopathic arthritis associated with interstitial lung disease (SJIA-LD) represents a highly morbid subset of SJIA for which effective therapies are lacking. We report the case of a patient with refractory SJIA-LD who underwent treatment with MAS-825, an investigational bispecific monoclonal antibody targeting IL-1ß and IL-18. MAS-825 treatment was associated with a marked reduction in total IL-18 and free IL-18 in both serum and bronchoalveolar lavage fluid (BAL). Baseline oxygen saturation, exercise tolerance, and quality of life metrics improved after treatment with MAS-825, while pulmonary function testing remained stable. Following treatment, the BAL showed no evidence of pulmonary alveolar proteinosis and inflammatory infiltrates were markedly reduced, reflected by decreased numbers of CD4 T-cells, CD8 T-cells, and macrophages. The patient was able to wean entirely off systemic corticosteroids and other biologics after 10 months of treatment with MAS-825 and experienced no side effects of the drug. This case demonstrates improvement in pulmonary symptoms, lung inflammation, and burden of immunomodulatory therapy after treatment with MAS-825 and suggests that simultaneous targeting of both IL-1ß and IL-18 may be a safe and effective treatment strategy in SJIA-LD.
Asunto(s)
Artritis Juvenil , Enfermedades Pulmonares Intersticiales , Síndrome de Activación Macrofágica , Humanos , Interleucina-18/uso terapéutico , Artritis Juvenil/complicaciones , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Calidad de Vida , Síndrome de Activación Macrofágica/diagnósticoRESUMEN
Traumatic brain injury (TBI) leads to lasting brain dysfunction with chronic neuroinflammation typified by nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome activation in microglia. This study probed whether a single intranasal (IN) administration of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs) naturally enriched with activated microglia-modulating miRNAs can avert chronic adverse outcomes of TBI. Small RNA sequencing confirmed the enrichment of miRNAs capable of modulating activated microglia in hMSC-EV cargo. IN administration of hMSC-EVs into adult mice ninety minutes after the induction of a unilateral controlled cortical impact injury resulted in their incorporation into neurons and microglia in both injured and contralateral hemispheres. A single higher dose hMSC-EV treatment also inhibited NLRP3 inflammasome activation after TBI, evidenced by reduced NLRP3, apoptosis-associated speck-like protein containing a CARD, activated caspase-1, interleukin-1 beta, and IL-18 levels in the injured brain. Such inhibition in the acute phase of TBI endured in the chronic phase, which could also be gleaned from diminished NLRP3 inflammasome activation in microglia of TBI mice receiving hMSC-EVs. Proteomic analysis and validation revealed that higher dose hMSC-EV treatment thwarted the chronic activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway by IL-18, which decreased the release of proinflammatory cytokines. Inhibition of the chronic activation of NLRP3-p38/MAPK signaling after TBI also prevented long-term cognitive and mood impairments. Notably, the animals receiving higher doses of hMSC-EVs after TBI displayed better cognitive and mood function in all behavioral tests than animals receiving the vehicle after TBI. A lower dose of hMSC-EV treatment also partially improved cognitive and mood function. Thus, an optimal IN dose of hMSC-EVs naturally enriched with activated microglia-modulating miRNAs can inhibit the chronic activation of NLRP3-p38/MAPK signaling after TBI and prevent lasting brain dysfunction.