Revisión sistemática de "miocinas y regulación metabólica" / A systematic review of "myokines and metabolic regulation"

Malos hábitos como el sedentarismo, obesidad o sobrealimentación, se relacionan a la evolución de estados pro-inflamatorios crónicos, principal factor de riesgo para el desarrollo de enfermedades crónicas no transmisibles (ECNT). Sin embargo, modificar únicamente el peso corporal no reduce el riesgo, es necesario también aumentar la masa muscular, dando a entender que existe una relación benéfica asociada a este tejido que no está totalmente dilucidada. Durante los últimos años, las explicaciones celulares más interesantes se han enfocado en la producción de citokinas musculares denominadas miokinas, dentro de las que se destacan la interleucina 6, el factor inhibidor de la leucemia, entre otras recientemente estudiadas como lo son la mionectina y la musclina. Debido a los múltiples avances, se realiza una revisión que pretende: presentar los hallazgos más recientes y representativos acerca de las miokinas, corregir conceptos y demostrar su aplicabilidad en la prescripción del ejercicio físico para la salud

Bad habits such as sedentary lifestyle, obesity or overfeeding, are related to the production of chronic pro-inflammatory states, the main risk factor for the development of chronic noncommunicable diseases (CNCD). However, modifying only the body weight does not reduce the risk, it is necessary to increase muscle mass, this implies there is a beneficial relationship associated with the muscle tissue that is not fully elucidated. During the last years, the most interesting cellular explanations have focused on the production of muscle cytokines called myokines, among which stand out interleukin 6, the inhibitory factor of leukemia, with others recently studied such as mionectine and muscline. Due to the multiple advances, this intends to present the most recent and representative findings about myokines, correct concepts and demonstrate their applicability in the prescription of physical exercise for health

Concentraciones de interleucina-15 en preeclámpticas y embarazadas normotensas sanas / Interleukin-15 concentrations in preeclamptic and healthy normotensive pregnant patients

Objetivo Comparar las concentraciones de interleucina-15 en pacientes con preeclampsia y embarazadas normotensas sanas. Método Se seleccionó un total de 100 pacientes. Se incluyeron 50 pacientes preeclámpticas como los casos (grupo A) y un grupo control seleccionado por tener una edad y un índice de masa corporal similares al grupo de estudio que consistió en 50 embarazadas normotensas sanas (grupo B). Las muestras de sangre se recolectaron en todas las pacientes antes del parto e inmediatamente después del diagnóstico en el grupo B para determinar las concentraciones de interleucina-15.ResultadosNo se encontraron diferencias significativas con relación a la edad materna, edad gestacional e índice de masa corporal al momento de la toma de la muestra (p=ns). Se encontraron diferencias estadísticamente significativa en las concentraciones de interleucina-15 entre las pacientes en el grupo de estudio (grupo A; 3,21±0,79pg/ml) y las pacientes del grupo control (grupo B; 2,26±0,24pg/ml; p<0,05). Se observó una correlación moderada, positiva y significativa con los valores de presión arterial sistólica (r=0,584; p<0,05) y con los valores de presión arterial diastólica (r=0,589; p<0,05).Conclusiones Las preeclámpticas presentaron concentraciones significativamente más altas de interleucina-15 al compararlo con embarazadas normotensas sanas (AU)

Objective To compare interleukin-15 concentrations in preeclamptic patients and healthy normotensive pregnant women. Method A total of 100 patients were selected. Fifty preeclamptic patients were selected as cases (group A) and 50 normotensive pregnant women with a similar age and body mass index to the study group were selected as controls (group B). Blood samples were collected before labor in all patients and immediately after diagnosis in group B to determine interleukin-15 concentrations. Results There were no significant differences in maternal age, gestational age or body mass index at sample extraction (p=ns). Interleukin-15 concentrations were significantly higher in patients in the study group (group A; 3.21±0.79pg/ml) than in those in the control group (group B; 2.26±0.24pg/ml; p<0.05). There was a moderate, positive and significant correlation with systolic blood pressure values (r=0.584; p<0.05) and diastolic blood pressure values (r=0.589; p<0.05).ConclusionsInterleukin-15 concentrations were significantly higher in preeclamptic patients than in healthy normotensive pregnant women (AU)

Novedades en enfermedad celíaca / Updates on coeliac disease

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Kill the Killers: terapia con células Natural Killer en pacientes pediátricos con cáncer refractario / Kill the Killers: Natural Killer cells therapy against paediatric refractory solid tumours

Introducción: En el momento actual, los tumores sólidos refractarios al tratamiento convencional constituyen la principal causa de muerte en la edad pediátrica. Por tanto, es necesario desarrollar y consolidar nuevos tratamientos. Las células Natural Killer (NK) constituyen la primera línea de defensa del sistema inmune frente al desarrollo de células tumorales. Planteamos una nueva estrategia de terapia celular antitumoral en niños con cánceres refractarios, inmunoterapia con células NK estimuladas con interleucina 15 (IL-15). Pacientes y Métodos: En 22 pacientes pediátricos con tumores sólidos refractarios y en controles sanos determinamos mediante citometría de flujo multiparamétrica y fluorescencia resuelta en el tiempo, el fenotipo y la actividad citotóxica de las células NK, respectivamente. En ratones inmunodeficientes desarrollamos un modelo de neuroblastoma metastático muy agresivo y terapia de rescate con células Natural Killer estimuladas con IL-15. Resultados: Los pacientes pediátricos con cáncer refractario tienen un mayor porcentaje de células NK bright y una menor actividad citotóxica. La estimulación con IL-15 mejora la citotoxicidad in vitro y disminuye la carga tumoral in vivo. Conclusiones: Las células NK estimuladas con IL-15 constituyen una prometedora estrategia antitumoral (AU)

Introduction: Refractory solid tumours lead children deaths. To change this statement, new treatments should be developed. Natural Killer cells constitute the first line of defence against tumour cells. We propose a new strategy for antitumor cell therapy in children with refractory solid malignancies: IL-15 stimulated NK cells. Patients and methods: 22 paediatric patients suffering refractory solid tumours participate in this study. We compare NK cell subsets and K562 cytotoxicity in patients and sex-age pair’s healthy controls. We use multiparametric flow and time-resolved fluorescent, respectively. In immunocompromised mice we developed an aggressive human metastatic neuroblastoma model and IL-15 stimulated NK cells rescue. Results: Patients had higher NK bright cells subset and lower NK cytotoxicity than healthy controls. IL-15 stimulated NK cells improved NK cell cytotoxicity in vitro and decreased tu-mour burden in vivo. Conclusions: IL-15 stimulated NK cells may constitute a new cell therapy tool for paediatric refractory tumours (AU)

Ascorbate-dependent decrease of the mucosal immune inflammatory response to gliadin in coeliac disease patients

Background: The IL-15/NF-KappaB axis has an important role in coeliac disease (CD) and may represent a molecular target for immunomodulation. Ascorbate (vitamin C) is known to show inhibitory effects on NF-KappaB. Therefore, we studied if ascorbate supplementation to gliadin gliadin-stimulated biopsy culture could down-regulate the mucosal immune response to gliadin in CD. Methods: Duodenal biopsy explants from treated CD patients were gliadin challenged in vitro (100ìg/ml) with and without 20mM ascorbate. An extra tissue explant in basal culture was used as internal control. Secretion levels of nitrites (3h), and IFNGamma, TNFalpha, IFNalpha, IL-17, IL-13, and IL-6 (24h) were measured on the supernatants. IL-15 was assayed by western-blot on whole protein duodenal explants. Results: The addition of ascorbate to in vitro culture gliadin-challenged biopsies blocked the secretion of nitrites (p=0.013), IFNGamma (p=0.0207), TNFalpha (p=0.0099), IFNá (p=0.0375), and IL-6 (p=0.0036) compared to samples from non-ascorbate supplemented culture. Cytokine secretion was downregulated by ascorbate even to lower values than those observed in basal cultures (IFNGamma: p=0.0312; TNFalpha: p=0.0312; IFNá: p=0.0312; and IL-6: p=0.0078). Gliadin-challenge induced IL-15 production in biopsies from treated CD patients, while the addition of ascorbate to culture medium completely inhibited IL-15 production. Moreover, the inhibition of IL-15 by ascorbate took place even in the only treated CD-patient who had basal IL-15 production. Conclusions: Ascorbate decreases the mucosal inflammatory response to gluten in an intestinal biopsy culture model, so it might have a role in future supplementary therapy in CD(AU)

Interleukin-15 enhances T-cell responses by stimulation with dendritic cells

INTRODUCTION: Cytokines play important roles in regulating immune responses. Interleukin-2 (IL-2) has usually been used as an adjuvant to enhance antitumour immune responses. However, its crucial role in activation-induced cell death, inhibition of homeostatic proliferation of CD8+ memory T cells and its notable biological side effects impair its prospect of application. IL-15 has several similar functions to IL-2 and shows potential advantages over IL-2, and is being investigated to enhance antitumour dendritic cell (DC) vaccine strategies in our ongoing studies. OBJECTIVE: In this preliminary study, we evaluated the ability of IL-15, compared with IL-2, to act as an adjuvant to enhance T-cell responses activated by DCs in vitro. MATERIALS AND METHODS: Bone marrow-derived DCs (BMDCs) were pulsed with tumour antigens and used to stimulate lymphocyte responses in the presence of IL-15 or IL-2. The activated T lymphocytes were examined by flow cytometric analysis, and interferon-γ (IFN-γ) enzyme-linked immunospot and cytotoxicity assays. RESULTS: IL-15 was observed to activate lymphocytes with comparable phenotype characteristics of activated/memory CD8+ lymphocytes, compared with IL-2. Both in primary and secondary stimulation with DCs, when using IL-15 as an adjuvant, activated lymphocytes showed higher proportions of IFN-γ-secreting subsets. In secondary stimulation with BMDCs in the presence of IL-15, the activated lymphocytes showed a stronger cytotoxicity to antigen-specific tumour target cells. CONCLUSIONS: Our study suggested that IL-15 might be a prospective adjuvant for a DC vaccine strategy against cancers. The further observation that IL-15 acts as an adjuvant for an antitumour DC vaccine strategy is worth investigating (AU)

El bloqueo terapéutico del factor de necrosis tumoral disminuye la concentración sérica de interleucina 15 en pacientes con artritis reumatoide / The therapeutic blockade of TNF reduces serum levels of interleukin 15 in patients with rheumatoid arthritis

Objetivo: Analizar el efecto de la terapia con agentes inhibidores del factor de necrosis tumoral (TNF) en la concentración sérica de interleucina 15 (IL-15) y determinar si los valores basales de ésta o su variación con el tratamiento predicen la respuesta clínica a los anti-TNF. Pacientes y método: Se estudió a 75 pacientes con artritis reumatoide que iban a iniciar tratamiento con anti-TNF. Se recogieron muestras de suero previas y a los 3 meses de tratamiento. La concentración de IL-15 se cuantificó mediante enzimoinmunoanálisis. Tanto en la visita basal como en la final se recogieron parámetros clínicos y analíticos que permitieran calcular el DAS28. También se recogieron variables sociodemográficas y otras relacionadas con la enfermedad, como factor reumatoide, número de fármacos previos, etc. Se definió remisión como un DAS28 < 2,6 y respuesta clínica relevante, como una disminución del DAS28 > 1,2. Resultados: La concentración de IL-15 se relacionó de forma significativa con un mayor uso de fármacos modificadores de la enfermedad durante el seguimiento de los pacientes. También se observó una disminución significativa de la IL-15 a los 3 meses de tratamiento con anti-TNF. Sin embargo, los valores basales de IL-15 y su disminución con el tratamiento no se relacionaron con la respuesta a los anti-TNF o la consecución de remisión clínica. Conclusiones: Nuestros datos parecen confirmar los obtenidos in vitro, que indican que el TNF está implicado en la modulación de la expresión de IL-15. No obstante, la medición de la concentración sérica de IL-15 no parece ser de utilidad para seleccionar a los pacientes candidatos a terapia anti-TNF (AU)

Objective: To analyze the effect of the TNF blocking agents (aTNF) on the serum levels of interleukin 15 (IL-15). To determine whether baseline IL15 serum levels or their response to aTNF therapy can predict the clinical response to this treatment. Patients and method: We studied 75 patients suffering from rheumatoid arthritis that were selected to start aTNF therapy. Serum samples were obtained at baseline visit and after three months of aTNF treatment. Measurement of IL-15 serum concentration was performed through immune-enzyme assay. We collected the clinical and analytical parameters needed to calculate DAS28 both at baseline and final visit, as well as sociodemographic variables and other such as rheumatoid factor, previous disease modifying anti-rheumatic drugs (DMARD), etc. We defined remission as a DAS28 < 2.6 and clinical response when the decrease in DAS28 value was higher than 1.2. Results: There was a significant correlation between IL-15 serum level and the number of previous DMARD. We also detected a significant decrease in the concentration of serum IL-15 after three months of treatment with aTNF. However, neither the baseline IL-15 serum level nor the decrease in the concentration of IL-15 were associated with a specific pattern of response to aTNF. Conclusions: Our data seem to support previous in vitro findings suggesting that TNF is involved in the regulation of IL-15 expression. Nevertheless, the measurement of IL-15 serum levels does not seem to be a useful tool to select those patients that should be treated with aTNF therapy (AU)

Citocinas en la patogenia de la enfermedad celíaca / Cytokines in the pathogeny of celiac disease

La enfermedad celíaca se manifiesta por una enteropatía causada por la intolerancia al gluten, una familia de proteínas presente en el trigo y otros cereales. Tras la activación de los linfocitos T del intestino delgado en individuos predispuestos, se ponen en marcha mecanismos inflamatorios regulados por el balance entre citocinas inflamatorias de perfil Th1, como el interferón gamma (IFN*), el factor de necrosis tumoral alfa (TNF*), la interleucina (IL)-15 e IL-18, y otras reguladoras como el factor transformador del crecimiento beta (TGFß) e IL-10. Estas citocinas, además de incrementar el número de células del sistema inmunitario en la mucosa intestinal y el grado de activación, regulan la actividad de los factores de crecimiento epitelial y de las metaloproteinasas, moléculas encargadas de mantener y renovar la estructura de la mucosa, que en situaciones de inflamación provocan la lesión intestinal que conduce al síndrome de malabsorción

Celiac disease is manifested by an enteropathy caused by intolerance to gluten, a family of proteins found in wheat and other cereals. Following intestinal T-cell activation in predisposed individuals, different inflammatory mechanisms are triggered under the control of the cytokine balance including those with a pro-inflammatory Th1 pattern such as IFN*, TNF*, IL-15 and IL-18; and regulatory cytokines such as TGFß and IL-10. These cytokines, besides increasing the intensity of the activation and the number of immune cells within the intestinal mucosa, regulate the activity of epithelial growth factors and metalloproteinases, a group of molecules involved in the maintenance and turnover of the intestinal mucosa structure; in inflammatory conditions, they also induce the intestinal lesion responsible for malabsorption syndrome