RESUMEN
Specific features of IL-6 signal transduction were studied in 89 patients with lung damage of varying degrees during the first COVID-19 pandemic wave. The levels of IL-6 signaling components (IL-6, sIL-6R, and sgp130) and highly sensitive C-reactive protein (hsCRP) were examined in patients with intact lungs (CT-0), mild (CT-1), moderate (CT-2), moderate to severe (CT-3), and severe (CT-4) lung damage. Seventy patients were re-examined 3-7 months after discharge from the hospital. The IL-6 and hsCRP levels increased several times with severing lung damage severity. In patients with CT-3, sIL6-R increased statistically significantly and remained high in CT-4 patients. sgp130 levels were lower in CT-1 and CT-2 patients and higher in CT-3 and CT-4 patients compared to CT-0 patients. We revealed a positive correlation between IL-6 and hsCRP levels in CT-1, CT-2, and CT-3 patients. In CT-3 patients, sIL-6R levels positively correlated with IL-6 concentration. The studied parameters decreased considerably in all patients 3-7 months after discharge. It can be suggested that IL-6 classic-signaling is predominant in CT-1 and CT-2, while trans-signaling prevails in CT-3. Disorders in regulatory mechanisms of IL-6 signaling occur in CT-4, which prevents physiological elimination of IL-6 hyperactivity. The results obtained are preliminary and require a broader study.
Asunto(s)
Proteína C-Reactiva , COVID-19 , Receptor gp130 de Citocinas , Interleucina-6 , Transducción de Señal , Humanos , Interleucina-6/sangre , COVID-19/inmunología , COVID-19/sangre , COVID-19/complicaciones , COVID-19/patología , Proyectos Piloto , Masculino , Femenino , Proteína C-Reactiva/metabolismo , Persona de Mediana Edad , Receptor gp130 de Citocinas/sangre , Receptor gp130 de Citocinas/metabolismo , Pulmón/patología , Pulmón/inmunología , SARS-CoV-2 , Anciano , Adulto , Receptores de Interleucina-6/sangre , Receptores de Interleucina-6/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. METHODS: The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. RESULTS: The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. DISCUSSION: Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients.
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Biomarcadores , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Humanos , Femenino , Masculino , Adulto , Esclerosis Múltiple Recurrente-Remitente/sangre , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Biomarcadores/sangre , Osteopontina/sangre , Factor Activador de Células B/sangre , Metaloproteinasa 2 de la Matriz/sangre , Receptor gp130 de Citocinas/sangre , Adulto JovenRESUMEN
Cytokines play a major role in the pathogenesis and progression of psoriasis. Interleukin (IL)-30 is a multifunctional cytokine. It binds to glycoprotein 130 (GP130) and inhibits the GP130 signaling pathways of psoriasis associated cytokines such as IL-6, IL-11, and IL-27. The study intended to assess associations of IL-30 and GP130 with the risk of psoriasis and Psoriasis Area Severity Index (PASI) score. Therefore, we measured the serum levels of IL-30 and GP130 in psoriasis patients and in a control group. An enzyme linked immunosorbent assay (ELISA) technique was used to measure IL-30 and GP130 levels in the serum of 43 patients and 43 normal controls. Statistical analysis of IL-30 and GP130 serum levels among patients and control groups and their correlation with PASI scores were performed. IL-30 serum levels showed a significant increase in patients with psoriasis compared with controls (p < 0.001) and a positive correlation with PASI scores. While serum levels of GP130 were not different in psoriatic patients and in the control group. Furthermore, the receiver operating characteristic (ROC) curve showed that IL-30 had diagnostic ability for prediction of psoriasis in comparison to controls, at cut of point of >14.34 showed a sensitivity of 97.7%, 100% specificity. In conclusion, IL-30 was elevated in psoriasis patients than controls, therefore, it can be considered a sensitive biomarker for diagnosis of psoriasis.
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Interleucina-27 , Psoriasis , Humanos , Receptor gp130 de Citocinas/sangre , Receptor gp130 de Citocinas/química , Citocinas , Interleucina-27/sangre , Interleucina-27/química , Interleucinas , Psoriasis/diagnóstico , BiomarcadoresRESUMEN
Acute cellular rejection (ACR) after liver transplantation (LT) goes along with allograft dysfunction, which is diagnosed by liver biopsy and concomitant histological analysis, representing the gold standard in clinical practice. Yet, liver biopsies are invasive, costly, time-intensive and require expert knowledge. Herein we present substantial evidence that blood plasma residing peripheral liver-derived extracellular particles (EP) could be employed to diagnose ACR non-invasively. In vitro experiments showed organ-specific EP release from primary human hepatocytes under immunological stress. Secondly, analysis of consecutive LT patients (n=11) revealed significant heightened EP concentrations days before ACR. By conducting a diagnostic accuracy study (n = 69, DRKS00011631), we explored the viability of using EP as a liquid biopsy for diagnosing ACR following LT. Consequently, novel EP populations in samples were identified using visualization of t-distributed stochastic neighbor embedding (viSNE) and self-organizing maps (FlowSOM) algorithms. As a result, the ASGR1+CD130+Annexin V+ EP subpopulation exhibited the highest accuracy for predicting ACR (area under the curve: 0.80, 95% confidence interval [CI], 0.70-0.90), with diagnostic sensitivity and specificity of 100% (95% CI, 81.67-100.0%) and 68.5% (95% CI, 55.3-79.3%), respectively. In summary, this new EP subpopulation presented the highest diagnostic accuracy for detecting ACR in LT patients.
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Anexina A5/sangre , Receptor de Asialoglicoproteína/sangre , Receptor gp130 de Citocinas/sangre , Rechazo de Injerto/sangre , Rechazo de Injerto/diagnóstico , Trasplante de Hígado/efectos adversos , Adulto , Anciano , Biomarcadores/sangre , Células Cultivadas , Femenino , Hepatocitos/inmunología , Hepatocitos/metabolismo , Humanos , Biopsia Líquida/métodos , Hígado/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Trasplante Homólogo/efectos adversosRESUMEN
[Figure: see text].
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Mediadores de Inflamación/sangre , Interleucina-6/sangre , Infarto del Miocardio/sangre , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Receptor gp130 de Citocinas/sangre , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Pronóstico , Receptores de Interleucina-6/sangre , Sistema de Registros , Medición de Riesgo , Fumar/efectos adversos , Suecia/epidemiología , Factores de TiempoRESUMEN
Allergic rhinitis (AR) and allergic asthma (AA) exhibit similar inflammatory response in the airways. However, the remodelling is more extensive in the lower airways, suggesting that the inflammation itself is not sufficient for allergic phenotype. We aimed to analyse whether the expression of selected 27 inflammatory and fibrosis-related proteins may be altered in AR and AA in the paediatric population and whether the expression pattern is either similar (due to the inflammation) or disease-specific (due to the remodelling). We analysed 80 paediatric subjects: 39 with AA, 21 with AR and 20 healthy children. The diagnosis of AR and AA was based on clinical manifestation, lung function, positive skin prick tests and increased immunoglobulin E levels. Serum levels of selected inflammatory proteins were measured with custom Magnetic Luminex Assay. Statistical analysis was performed in Statistica v.13. CCL2/MCP1, GM-CSF, gp130 and periostin concentrations were significantly lower, whereas IL-5 levels were higher in AA compared to the control group. CD-40L, CHI3L1/YKL-40, EGF, GM-CSF and periostin levels were significantly decreased in patients with AR than in the control group. Comparison of AA and AR patients revealed significant changes in CHI3L1/YKL-40 (P = 0.021), IL-5 (P = 0.036), periostin (P = 0.013) and VEGFα (P = 0.046). Significantly altered proteins were good predictors to distinguish between AA and AR (P < 0.001, OR 46.00, accuracy 88.57%). Our results suggest that the expression of four fibrotic proteins was significantly altered between AA and AR, suggesting possible differences in airway remodelling between upper and lower airways.
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Asma/sangre , Rinitis Alérgica/sangre , Adolescente , Asma/inmunología , Asma/patología , Asma/fisiopatología , Moléculas de Adhesión Celular/sangre , Niño , Proteína 1 Similar a Quitinasa-3/sangre , Receptor gp130 de Citocinas/sangre , Citocinas/sangre , Femenino , Fibrosis , Humanos , Inmunoglobulina E/sangre , Masculino , Sistema Respiratorio/patología , Rinitis Alérgica/inmunología , Rinitis Alérgica/patología , Rinitis Alérgica/fisiopatología , Pruebas Cutáneas , Espirometría , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
PURPOSE: Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling. METHODS: Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t-distributed stochastic neighbor embedding (t-SNE). RESULTS: OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals (p = 1.8 × 10-13 to 4 × 10-8). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 (p = 2.8 × 10-13), IL6R (p = 1.1 × 10-9), TNFR1 (p = 2.5 × 10-10), and TNFR2 (p = 5.7 × 10-9), levels indistinguishable from controls (p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients. CONCLUSIONS: Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients.
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Presión de las Vías Aéreas Positiva Contínua , Enfermedades Neurodegenerativas/epidemiología , Receptores de Citocinas/sangre , Apnea Obstructiva del Sueño/terapia , Adulto , Anciano , Receptor gp130 de Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Interleucina-6/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Apnea Obstructiva del Sueño/sangre , Resultado del TratamientoRESUMEN
Interleukin (IL) 6 contributes to atherosclerotic plaque development through IL6 membrane-bound (IL6R and gp130) and soluble (sIL6R and sgp130) receptors. We investigated IL6 receptor expression in carotid plaques and its correlation with circulating IL6 and soluble receptor levels. Plasma samples and carotid plaques were obtained from 78 patients in the Biobank of Karolinska Endarterectomies study. IL6, sIL6R, and sgp130 were measured in plasma and IL6, IL6R, sIL6R, GP130, and sGP130-RAPS (sGP130) gene expression assessed in carotid plaques. Correlations between plaque IL6 signaling gene expression and plasma levels were determined by Spearman's correlation. Differences in plasma and gene expression levels between patients with (n = 53) and without (n = 25) a history of a cerebral event and statin-treated (n = 65) and non-treated (n = 11), were estimated by Kruskal-Wallis. IL6 and its receptors were all expressed in carotid plaques. There was a positive, borderline significant, moderate correlation between plasma IL6 and sIL6R and the respective gene expression levels (rho 0.23 and 0.22, both p = 0.05). IL6R expression was higher in patients with a history of a cerebrovascular event compared to those without (p = 0.007). Statin-treated had higher IL6R, sIL6R, and sGP130 expression levels and plasma sIL6R compared to non-treated patients (all p < 0.05). In conclusion, all components of the IL6 signaling pathways are expressed in carotid artery plaques and IL6 and sIL6R plasma levels correlate moderately with IL6 and sIL6R. Our data suggest that IL6 signaling in the circulation might mirror the system activity in the plaque, thus adding novel perspectives to the role of IL6 signaling in atherosclerosis.
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Arterias Carótidas/metabolismo , Estenosis Carotídea/metabolismo , Receptor gp130 de Citocinas/metabolismo , Interleucina-6/metabolismo , Placa Aterosclerótica , Receptores de Interleucina-6/metabolismo , Anciano , Biomarcadores/metabolismo , Arterias Carótidas/cirugía , Estenosis Carotídea/sangre , Estenosis Carotídea/genética , Estenosis Carotídea/terapia , Estudios Transversales , Receptor gp130 de Citocinas/sangre , Receptor gp130 de Citocinas/genética , Endarterectomía Carotidea , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Interleucina-6/sangre , Interleucina-6/genética , Masculino , Receptores de Interleucina-6/sangre , Receptores de Interleucina-6/genética , Transducción de SeñalRESUMEN
OBJECTIVE: The objective of the present study was to evaluate the serum levels of soluble oncostatin M (OSM), OSM receptor (sOSMR) and glycoprotein130 (sgp130) in patients with systemic sclerosis (SSc), and the possible associations and correlations with clinical parameters. METHODS: Serum levels of OSM, sOSMR and sgp130 were evaluated by ELISA in eighty-four SSc patients and eighty-four healthy volunteers. RESULTS: SSc patients had significantly elevated levels of sOSMR and sgp130 when compared with healthy individuals (p < 0.0001 and p = 0.025, respectively). Diffuse cutaneous SSc and limited cutaneous SSc patients also presented higher levels of sOSMR when compared with healthy individuals (p = 0.003 and p = 0.0001, respectively). Patients with digital ulcers presented higher levels of sOSMR when compared to those without ulcers (p = 0.034). However, sOSMR levels were lower in patients with esophageal dysfunction than patients without this involvement (p = 0.038). OSM levels were undetectable in serum from SSc patients and healthy volunteers. CONCLUSION: Serum levels of sOSMR and sgp130 are elevated in patients with systemic sclerosis. In addition, associations were observed with important clinical manifestations, suggesting that sOSMR is a candidate biomarker of this disease. More studies are needed to clarify the functions of IL-6 family cytokines in systemic sclerosis.
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Biomarcadores , Receptor gp130 de Citocinas/sangre , Subunidad beta del Receptor de Oncostatina M/sangre , Esclerodermia Sistémica/sangre , Estudios de Casos y Controles , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Fibrosis , Humanos , Esclerodermia Sistémica/diagnósticoRESUMEN
The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 and markers of subclinical atherosclerosis. The study is based on IMPROVE (n = 3703), a cardiovascular multicentre study designed to investigate the determinants of carotid intima media thickness, a measure of subclinical atherosclerosis. Genomic DNA was genotyped by the CardioMetaboChip and ImmunoChip. About 360,842 SNPs were tested for association with log-transformed sgp130, using linear regression adjusted for age, gender, and population stratification using PLINK v1.07. A p value of 1 × 10-5 was chosen as threshold for significance value. In an exploratory analysis, SNPs associated with sgp130 were tested for association with c-IMT measures. We identified two SNPs significantly associated with sgp130 levels and 24 showing suggestive association with sgp130 levels. One SNP (rs17688225) on chromosome 14 was positively associated with sgp130 serum levels (ß = 0.03 SE = 0.007, p = 4.77 × 10-5) and inversely associated with c-IMT (c-IMTmean-max ß = -0.001 SE = 0.005, p = 0.0342). Our data indicate that multiple loci regulate sgp130 levels and suggest a possible common pathway between sgp130 and c-IMT measures.
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Aterosclerosis/sangre , Aterosclerosis/genética , Receptor gp130 de Citocinas/sangre , Receptor gp130 de Citocinas/genética , Anciano , Aterosclerosis/patología , Biomarcadores/sangre , Grosor Intima-Media Carotídeo , Femenino , Frecuencia de los Genes , Sitios Genéticos , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Interleucina-6/sangre , Interleucina-6/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Serum levels of interleukin-6 (IL-6) are increased in patients with type 2 diabetes (T2D). IL-6 exerts its pleiotropic effects via the IL-6 α-receptor (IL-6R), which exists in membrane-bound and soluble (sIL-6R) forms and activates cells via the ß-receptor glycoprotein 130 (gp130). The nonsynonymous single-nucleotide polymorphism (SNP) rs2228145 (Asp358Ala) within the IL6R locus is associated with T2D. The aim of this study was to determine whether sIL-6R in combination with soluble gp130 (sgp130) is able to form an IL-6-neutralizing buffer in healthy subjects and whether this is disturbed in T2D. We found that sIL-6R-sgp130 indeed forms an IL-6-neutralizing buffer in the serum of healthy humans, whose capacity is controlled by the SNP of the IL-6R. Circulating sIL-6R-sgp130 levels were lower in T2D subjects (P < 0.001), whereas IL-6 was high and inversely correlated with sIL-6R (r = -0.57, P < 0.001), indicating a severe disturbance of the buffer. This phenomenon is also observed in sex- and age-matched patients with both T2D and atherosclerosis but not in patients with atherosclerosis alone. In conclusion, sIL-6R and sgp130 serum levels were significantly lower in T2D patients compared with healthy subjects or atherosclerosis patients, although IL-6 levels were high. These data suggest that disturbance of the protective buffer may be closely associated with T2D pathophysiology.
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Receptor gp130 de Citocinas/sangre , Diabetes Mellitus Tipo 2/sangre , Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/sangre , Anciano , Sustitución de Aminoácidos , Aterosclerosis/sangre , Aterosclerosis/etiología , Estudios de Casos y Controles , Receptor gp130 de Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Células Hep G2 , Humanos , Interleucina-6/sangre , Interleucina-6/farmacología , Masculino , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Unión Proteica , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
OBJECTIVE: Clinical and laboratory studies have demonstrated that platelets become hyperactive and prothrombotic in conditions of inflammation. We have previously shown that the proinflammatory cytokine interleukin (IL)-6 forms a complex with soluble IL-6 receptor α (sIL-6Rα) to prime platelets for activation by subthreshold concentrations of collagen. Upon being stimulated with collagen, the transcription factor signal transducer and activator of transcription (STAT) 3 in platelets is phosphorylated and dimerized to act as a protein scaffold to facilitate the catalytic action between the kinase Syk and the substrate phospholipase Cγ2 (PLCγ2) in collagen-induced signaling. However, it remains unknown how collagen induces phosphorylation and dimerization of STAT3. METHODS AND RESULTS: We conducted complementary in vitro experiments to show that the IL-6 receptor subunit glycoprotein 130 (GP130) was in physical proximity to the collagen receptor glycoprotein VI (GPVI in membrane lipid rafts of platelets. This proximity allows collagen to induce STAT3 activation and dimerization, and the IL-6-sIL-6Rα complex to activate the kinase Syk and the substrate PLCγ2 in the GPVI signal pathway, resulting in an enhanced platelet response to collagen. Disrupting lipid rafts or blocking GP130-Janus tyrosine kinase (JAK)-STAT3 signaling abolished the cross-activation and reduced platelet reactivity to collagen. CONCLUSION: These results demonstrate cross-talk between collagen and IL-6 signal pathways. This cross-talk could potentially provide a novel mechanism for inflammation-induced platelet hyperactivity, so the IL-6-GP130-JAK-STAT3 pathway has been identified as a potential target to block this hyperactivity.
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Plaquetas/metabolismo , Receptor gp130 de Citocinas/sangre , Microdominios de Membrana/fisiología , Glicoproteínas de Membrana Plaquetaria/fisiología , Coagulación Sanguínea/efectos de los fármacos , Colágeno/farmacología , Receptor gp130 de Citocinas/química , Hemorreología , Humanos , Inmunoprecipitación , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/sangre , Fosfolipasa C gamma/sangre , Fosforilación , Agregación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/fisiología , Glicoproteínas de Membrana Plaquetaria/química , Mapeo de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional , Factor de Transcripción STAT3/sangreRESUMEN
INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is the most common type among renal cell carcinomas, and anti-angiogenic treatment is currently first line therapy in metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have major influence on patient's quality of life. The need for predictive biomarkers to select those patients most likely to respond to receptor tyrosine kinase inhibitors (rTKI) upfront is urgent. We investigated the predictive value of plasma interleukin-6 (pIL6), interleukin-6 receptor α (pIL6Rα) and interleukin 6 signal transducer (pIL6ST) in mccRCC patients treated with sunitinib. MATERIAL AND METHODS: Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Full blood samples were collected at baseline before start of sunitinib and after every second cycle of treatment during the study time. pIL6, pIL6R and pIL6ST at baseline and week 12 samples were analysed by ELISA. The predictive potential of the candidate markers was assessed by correlation with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. RESULTS: Low pIL6 at baseline was significantly associated with improved response to sunitinib (Fisher's exact test, p < 0.01). Furthermore, low pIL6 at baseline was significantly associated with improved PFS (log rank, pâ¯=â¯0.04). In addition, patients with a decrease in concentration of pIL6R between baseline and week 12 showed significantly improved PFS (log rank, pâ¯=â¯0.04) and patients with high pIL6ST at baseline showed significantly improved OS (log rank, pâ¯=â¯0.03). CONCLUSION: Low pIL6 at baseline in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.
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Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/secundario , Receptor gp130 de Citocinas/sangre , Interleucina-6/sangre , Neoplasias Renales/patología , Receptores de Interleucina-6/sangre , Sunitinib/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/sangre , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Calidad de Vida , Tasa de SupervivenciaRESUMEN
BACKGROUND AND AIMS: Myocardial infarction triggers an inflammatory response involved in cardiac repair. We studied the association of the interleukin 6 (IL-6) cascade with infarct size and cardiac function after ST-elevation myocardial infarction (STEMI). METHODS: In 369 STEMI patients IL-6, soluble IL-6 receptor (sIL-6R), and soluble glycoprotein (sgp) 130 were measured at baseline (hospital admission), 24 h, 2 weeks, 7 weeks, 4 months, and 1 year post-PCI and sIL-6R/IL-6 ratio was calculated. At 4 months, infarct size and left ventricular ejection fraction (LVEF) were assessed by magnetic resonance imaging. Diastolic function (E/e') was determined by echocardiography. RESULTS: Hospital admission levels for IL-6, sIL-6R, sgp 130 were 3.7 pg/ml (IQR 2.1-6.7 pg/ml), 51.6 ng/ml (IQR 37.3-69.0 ng/ml), and 332 ng/ml (IQR 280-399 ng/ml), respectively. 24 h after admission, IL-6 had increased threefold compared to baseline (p < 0.001) and returned below baseline (p < 0.001) 2 weeks after STEMI. sIL-6R and sgp130 levels at 24 h remained similar to baseline but were increased at 2 weeks (p < 0.001; p < 0.001, respectively). IL-6 and sIL-6R/IL-6 ratio at 24 h were independently associated with infarct size [ß 5.4 (95% CI 3.3-7.5); p < 0.001, ß - 4.0 (95% CI - 6.1 to - 1.9); p < 0.001, respectively]. Higher levels of IL-6 at 24 h were associated with lower LVEF [ß - 4.2 (95% CI -6.7 to - 1.8); p = 0.001]. CONCLUSIONS: Higher IL-6 and lower sIL-6R/IL-6 ratio early after presentation with STEMI are indicative for larger infarct size and decreased cardiac function at 4 months.
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Interleucina-6/sangre , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/terapia , Volumen Sistólico , Función Ventricular Izquierda , Anciano , Biomarcadores/sangre , Receptor gp130 de Citocinas/sangre , Ecocardiografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Miocardio/patología , Intervención Coronaria Percutánea/efectos adversos , Receptores de Interleucina-6/sangre , Recuperación de la Función , Factores de Riesgo , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/fisiopatología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Aims: The pro-inflammatory response to interleukin 6 (IL6) trans-signalling in atherosclerosis is driven by the IL6 and soluble IL6 receptor (sIL6R) binary complex. The binary IL6:sIL6R complex is inactivated by sgp130 through the formation of the ternary IL6:sIL6R:sgp130 complex. The aim of this study was to investigate if IL6 trans-signalling, estimated by a ratio between the binary and ternary complexes, associates with the risk of future cardiovascular events (CVE) in a Swedish cohort of 60-year-old men and women (n = 4232). Methods and results: Binary and ternary complex levels expressed in nanomol/Litre were derived from serum concentrations of IL6, sIL6R, and sgp130. Cox regression models were used to assess the risk of CVE (myocardial infarction, angina pectoris, and ischaemic stroke, n = 525), expressed as hazard ratio (HR) with 95% confidence interval (CI), associated with increasing circulating levels of the three molecules and with the binary/ternary complex ratio. Estimates were adjusted for the common cardiovascular (CV) risk factors. To assess the level of IL6-trans-signalling, we estimated the binary/ternary complex ratio and then analysed the association with CVE risk. A ratio higher than the median, representing a relative excess of the active binary complex was associated with increased CVE risk (adjusted HR 1.44, 95% CI 1.21-1.72). Conclusion: The ratio between the functional moieties of IL6 trans-signalling, IL6:sIL6R, and IL6:sIL6R:sgp130, was associated with CVE risk indicating that it could be a promising marker of CV risk and possibly be used in selecting patients for anti-inflammatory therapy.
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Enfermedades Cardiovasculares/sangre , Receptor gp130 de Citocinas/sangre , Interleucina-6/sangre , Receptores de Interleucina-6/sangre , Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Transducción de Señal , Suecia/epidemiología , Factores de TiempoRESUMEN
The aim of this study was to measure the impact, at 24 h post-exercise, of a single exercise bout on plasma inflammatory markers such as calprotectin, IL-6, sIL-6 R, sgp130 and the hypothalamic-pituitary-adrenal (HPA) axis in children with juvenile idiopathic arthritis (JIA).Twelve children with JIA attended the laboratory on three consecutive days (control day, exercise day and 24 h post-exercise), including a 20-min exercise bout on a cycle-ergometer at 70% of max. HR at 8:30 a.m. on day 2. Plasma concentrations of calprotectin, IL-6, sIL-6 R, sgp130, cortisol, ACTH and DHEA were measured on venous blood samples taken every day.at rest and at 8:30, 8:50, 9:30, 10:30 a.m. and 12:00, 3:00, 5:30 p.m.A single exercise bout increased plasma calprotectin 1.7-fold (p<0.001) but did not increase IL-6 and soluble IL-6 receptors in short-term post-exercise recovery. However, at 24 h post-exercise, calprotectin, IL-6 and its receptors had decreased compared to control-day levels. There was a transient 2-fold increase in post-exercise self-evaluated pain (p=0.03) that disappeared in the evening without repercussions the following day.Physical activity in children with JIA results in a slight transient systemic inflammation but seems to be followed by counter-regulation at 24 h post-exercise with a decrease in proinflammatory markers.
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Artritis Juvenil/fisiopatología , Biomarcadores/sangre , Ejercicio Físico/fisiología , Adolescente , Hormona Adrenocorticotrópica/sangre , Artritis Juvenil/sangre , Niño , Receptor gp130 de Citocinas/sangre , Deshidroepiandrosterona/sangre , Progresión de la Enfermedad , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Interleucina-6/sangre , Complejo de Antígeno L1 de Leucocito/sangre , Masculino , Dimensión del Dolor , Sistema Hipófiso-Suprarrenal/fisiopatología , Receptores de Interleucina-6/sangre , Factores de TiempoRESUMEN
The use of blood biomarkers for stroke has been long considered an excellent method to determine the occurrence, timing, subtype, and severity of stroke. In this study, venous blood was obtained from ischemic stroke patients after stroke onset and compared with age and sex-matched controls. We used a multiplex panel of 37 inflammatory molecules, analyzed using Luminex MagPix technology, to identify the changes in plasma proteins after ischemic stroke. We identified eight key molecules that were altered within the blood of stroke patients as compared to controls. Plasma levels of interleukin 6 signal transducer (sIL-6Rß/gp130), matrix metalloproteinase-2 (MMP-2), osteopontin, sTNF-R1 and sTNF-R2 were significantly higher in stroke patients compared to controls. Interferon-ß, interleukin-28, and thymic stromal lymphopoietin (TSLP) were decreased in plasma from stroke patients. No other immunological markers were significantly different between patient groups. When stroke patients were treated with tissue plasminogen activator (t-PA), plasma levels of interferon-α2 significantly increased while interleukin-2 and pentraxin-3 decreased. The discriminatory power of the molecules was evaluated by receiver operating characteristic (ROC) analysis. According to ROC analysis, the best markers for distinguishing stroke occurrence were MMP-2 (AUCâ¯=â¯0.76, sensitivity 62.5%, specificity 88.5%), sTNF-R2 (AUCâ¯=â¯0.75, sensitivity 83.3%, specificity 65.3%) and TSLP (AUCâ¯=â¯0.81, sensitivity 66.7%, specificity 96.2%). Multivariate logistic regression, used to evaluate the combination of proteins, identified a biomarker panel with high specificity and sensitivity (AUCâ¯=â¯0.96, sensitivity 87.5%, specificity 96.2%). These results indicate a novel set of blood biomarkers that could be used in a panel to identify stroke patients and their responsiveness to therapeutic intervention.
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Proteínas Sanguíneas/metabolismo , Accidente Cerebrovascular/sangre , Anciano , Biomarcadores/sangre , Biomarcadores Farmacológicos/sangre , Isquemia Encefálica/sangre , Receptor gp130 de Citocinas/sangre , Femenino , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/sangre , Persona de Mediana Edad , Osteopontina/sangre , Curva ROC , Factores de Riesgo , Accidente Cerebrovascular/tratamiento farmacológico , Factor 1 Asociado a Receptor de TNF/sangre , Factor 2 Asociado a Receptor de TNF/sangre , Activador de Tejido Plasminógeno/uso terapéuticoRESUMEN
Objective: In a context of inflammatory disease such as juvenile idiopathic arthritis (JIA), we do not know what impact physical activity may have on a deregulated immune system. The objective is to measure the impact of a single bout of exercise on plasma inflammatory markers such as calprotectin, IL-6, sIL-6R, sgp130, and the hypothalamic-pituitary-adrenal axis in children with juvenile idiopathic arthritis. Methods: Twelve children with JIA performed a nonexercise control day and a consecutive day that included a 20 min exercise bout at 70% of max-HR at 08:30 am. Venous blood samples were taken at 08:30, 08:50, 09:30, 10:30 am, and 12:00 pm to measure plasma concentrations of calprotectin, IL-6, sIL-6R, sgp130, cortisol, and ACTH. Pain was evaluated at 08:30, 08:50 am, and 06:00 pm. Results: There was a transient twofold increase in postexercise self-evaluated pain (p = 0.03) that disappeared in the evening. A single bout of exercise resulted in a 1.7-fold increase in plasma calprotectin (p < 0.001) but not IL-6 and its soluble receptors. Calprotectin levels returned to baseline within 3 hours after cessation of exercise. Conclusion: Acute exercise in children with JIA induced slightly musculoskeletal leg pain and transient increased plasma calprotectin levels but not IL-6 levels. Trial registration in ClinicalTrials.gov, reference number NCT 02502539, registered on 29 May 2015.
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Artritis Juvenil/fisiopatología , Ejercicio Físico , Inflamación/fisiopatología , Interleucina-6/sangre , Complejo de Antígeno L1 de Leucocito/sangre , Adolescente , Área Bajo la Curva , Artritis Juvenil/terapia , Índice de Masa Corporal , Niño , Receptor gp130 de Citocinas/sangre , Femenino , Humanos , Inflamación/terapia , Pierna/patología , Masculino , Manejo del Dolor , Receptores de Interleucina-6/sangreRESUMEN
PURPOSE: Interleukin-6 (IL-6) production and signalling are increased in the inflamed mucosa in inflammatory bowel diseases (IBD). As published serum levels of IL-6 and its soluble receptors sIL-6R and sgp130 in IBD are from small cohorts and partly contradictory, we systematically evaluated IL-6, sIL-6R and sgp130 levels as markers of disease activity in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Consecutive adult outpatients with confirmed CD or UC were included, and their disease activity and medication were monitored. Serum from 212 CD patients (815 measurements) and 166 UC patients (514 measurements) was analysed, and 100 age-matched healthy blood donors were used as controls. RESULTS: IL-6 serum levels were significantly elevated in active versus inactive CD and UC, also compared with healthy controls. However, only a fraction of IBD patients showed increased serum IL-6. IL-6 levels ranged up to 32.7 ng/mL in active CD (> 5000-fold higher than in controls), but also up to 6.9 ng/mL in inactive CD. Increases in active UC (up to 195 pg/mL) and inactive UC (up to 27 pg/mL) were less pronounced. Associations between IL-6 serum levels and C-reactive protein concentrations as well as leukocyte and thrombocyte counts were observed. Median sIL-6R and sgp130 levels were only increased by up to 15%, which was considered of no diagnostic significance. CONCLUSIONS: Only a minority of IBD patients shows elevated IL-6 serum levels. However, in these patients, IL-6 is strongly associated with disease activity. Its soluble receptors sIL-6R and sgp130 do not appear useful as biomarkers in IBD.
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Receptor gp130 de Citocinas/sangre , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/sangre , Interleucina-6/sangre , Adulto , Bancos de Muestras Biológicas , Femenino , Alemania , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , MasculinoRESUMEN
The interleukin (IL)-6 biological system plays a key role in the pathogenesis of Paget disease (PD) of bone and pathological bone pain. Bone pain, particularly in the lower back region, is the most frequent symptom in patients with PD. This case-control study aimed to evaluate the relationship between the IL-6 system and low back pain (LBP) in patients with PD. We evaluated 85 patients with PD, with the disease localized in the lumbar spine, pelvis, and/or sacrum, and classified them based on the presence or absence of LBP, before and after aminobisphosphonate treatment. We also examined 32 healthy controls without LBP. Before treatment, IL-6 levels in patients with PD were higher than those in the controls, without difference between patients with or without LBP. Patients with PD with LBP (35/85) showed higher IL-6-soluble receptor (sIL-6R) and lower soluble glycoprotein (sgp) 130 levels compared with both patients with PD without LBP and controls (sIL-6R: 46.9 ± 7.4 vs 35.4 ± 8.6 vs 29.9 ± 4.2 ng/mL; sgp130: 307.2 ± 35.4 vs 341.4 ± 41.4 vs 417.1 ± 58.5 ng/mL, respectively). Paget disease remission, 6 months after treatment, is associated with LBP improvement. This phenomenon is associated with reduced sIL-6R levels and increased sgp130 levels in patients with PD with LBP at the baseline. Considering the biological properties of IL-6, sIL-6R, and sgp130, the results of the study suggest that the perception of LBP in patients with PD could be linked to an enhanced transmission of IL-6 signal in the specialized neural system activated by nociceptors.