Niveles de citoquinas megacariocitopoyéticas en pacientes con trombocitemia esencial y su relación con características clínicas y bioquímicas / Megakaryopoietic cytokine levels in patients with essential thrombocythemia and their relationship with clinical and biochemical features

La megacariocitopoyesis y la producción de plaquetas están regidas por factores de transcripción y citoquinas presentes en el microambiente medular. La trombocitemia esencial (TE) es una enfermedad mieloproliferativa crónica caracterizada por aumento del recuento de plaquetas e hiperplasia megacariocítica. En el presente trabajo se evaluaron los niveles de las citoquinas que participan en el desarrollo megacariocítico en plasma de pacientes con TE que se encontraban sin tratamiento y los de trombopoyetina (TPO) antes y durante el tratamiento con anagrelide. Las determinaciones se realizaron por técnica de ELISA. Dentro de las citoquinas involucradas en la etapa de proliferación, los niveles de interleuquina 3 (IL-3) se encontraron aumentados en los pacientes (p=0.0383) respecto al grupo control. Los niveles de factor estimulante de colonias granulocito-macrofágico y stem cell factor fueron normales. Dentro de las citoquinas con acción sobre la maduración megacariocítica, tanto la interleuquina 6 como la interleuquina 11 y la eritropoyetina estuvieron normales. Los niveles de TPO antes del tratamiento no difirieron del grupo control y durante el tratamiento aumentaron de manera no significativa. Los pacientes que presentaron agregación espontánea tuvieron niveles más altos de TPO que los que no lo hicieron (p=0.049). Los niveles de las citoquinas no tuvieron relación con ninguno de los parámetros clínicos ni de laboratorio evaluados. El aumento de los niveles de IL-3 podría contribuir al incremento en la proliferación megacariocítica en este grupo. La presencia simultánea de niveles más altos de TPO y trombocitosis sería un factor predisponente para la ocurrencia de agregación espontánea en los pacientes con TE

Megakaryopoiesis and platelet production are driven by transcription factors and cytokines present in bone marrow environment. Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by high platelet count and megakaryocytic hyperplasia. In the present work we evaluated plasmatic levels of cytokines involved in megakaryocytic development in a group of patients with ET that were not on treatment, as well as thrombopoietin (TPO) levels before and during anagrelide treatment. The assays were carried out using ELISA techniques. Among the cytokines mainly involved in proliferation of megakaryocytic progenitors, interleukin 3 (IL-3) levels were found increased in patients compared to normal controls (p=0.0383). Granulocyte-macrophage colony stimulating factor and stem cell factor levels were normal. Interleukin 6, as well as interleukin 11 and erythropoietin (EPO), cytokines mainly related to megakaryocytic maturation, were normal. Plasma TPO levels before treatment were within the normal range and increased during treatment but the difference was not statistically significant. Patients who displayed spontaneous platelet aggregation had higher plasma TPO levels compared to those who did not (p=0.049). We did not find any relationship between cytokine levels and clinical or laboratory parameters. The high IL-3 levels seen in some patients with ET could contribute to megakaryocytic proliferation. The simultaneous occurrence of higher TPO levels and elevated platelet count could be a predisposing factor for the development of spontaneous platelet aggregation in ET patients

Regulation of stem cell factor expression in inflammation and asthma

Stem cell factor (SCF) is a major mast cell growth factor, which could be involved in the local increase of mast cell number in the asthmatic airways. In vivo, SCF expression increases in asthmatic patients and this is reversed after treatment with glucocorticoids. In vitro in human lung fibroblasts in culture, IL-1beta, a pro-inflammatory cytokine, confirms this increased SCF mRNA and protein expression implying the MAP kinases p38 and ERK1/2 very early post-treatment, and glucocorticoids confirm this decrease. Surprisingly, glucocorticoids potentiate the IL-1beta-enhanced SCF expression at short term treatment, implying increased SCF mRNA stability and SCF gene transcription rate. This potentiation involves p38 and ERK1/2. Transfection experiments with the SCF promoter including intron1 also confirm this increase and decrease of SCF expression by IL-1beta and glucocorticoids, and the potentiation by glucocorticoids of the IL-1beta-induced SCF expression. Deletion of the GRE or kappaB sites abolishes this potentiation, and the effect of IL-1beta or glucocorticoids alone. DNA binding of GR and NF-kappaB are also demonstrated for these effects. In conclusion, this review concerns new mechanisms of regulation of SCF expression in inflammation that could lead to potential therapeutic strategy allowing to control mast cell number in the asthmatic airways.