RESUMEN
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) along with their blood lipid-lowering effect exhibit anti-inflammatory and immunomodulatory activity. We studied the effects of long-term (72-h or longer) exposure of human T lymphocytes in culture to atorvastatin and rosuvastatin (5-80 nM) on their functional activity. Treatment with statins inhibited PHA/IL-2-induced proliferation of CD4+ T lymphocytes isolated from the peripheral blood of healthy donors. This was accompanied by a decrease in the relative content of cells expressing active caspase-3. Addition of mevalonate or fetal bovine serum simultaneously with statins restored proliferative activity of cells. Culturing of CD4+ T lymphocytes with statins in the presence of IL-2 did not significantly affect the expression of chemokine receptors CCR4, CCR5, CXCR3, and CXCR4. Pretreatment with statins suppressed spontaneous and SDF-1-stimulated migration of CD4+ T lymphocytes, but little changed the content of intracellular phosphorylated protein kinases Akt, p38 and p42/44 (ERK1/2). The cellular effects of "lipophilic" atorvastatin were observed at lower concentrations compared to "hydrophilic" rosuvastatin.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Atorvastatina/farmacología , Linfocitos T CD4-Positivos/fisiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quimiotaxis de Leucocito/efectos de los fármacos , Humanos , Receptores CCR4/metabolismo , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR4/metabolismo , Rosuvastatina Cálcica/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
We examined the effects of 72-h exposure to atorvastatin and rosuvastatin in concentrations of 2-10 nM on the cytokine expression in LPS/IFNγ-activated monocyte/macrophages derived from peripheral blood monocytes of healthy donors by culturing in the presence of GM-CSF. Pretreatment with statins was found to inhibit cytokine production in monocytes/macrophages after activation, while the level of cytokine mRNA in cells did not decrease. The number of cells containing active caspase-3 decreased in the culture. Culturing of monocytes/macrophages with statins was accompanied by changes in cell morphology and deceleration of cell growth. Cellular effects of "lipophilic" atorvastastin were observed at lower concentration compared to "hydrophilic" rosuvastatin.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lipopolisacáridos/metabolismo , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Apoptosis , Atorvastatina/farmacología , Caspasa 3/metabolismo , Proliferación Celular , Células Cultivadas , Citocinas/metabolismo , Citometría de Flujo , Humanos , Inflamación , Interferón gamma/metabolismo , Leucocitos Mononucleares/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , ARN Mensajero/metabolismo , Rosuvastatina Cálcica/farmacologíaRESUMEN
AIM: Immune and inflammatory reactions contribute to the progression of atherosclerosis. The walls of the different arteries and segments of the arteries have heterogeneous haemodynamic and histological features. We aimed to explore the relationship between the circulating T-cell subsets and the abundance of carotid atherosclerosis in different segments of carotid arteries. METHODS: 70 patients underwent ultrasound duplex scanning to determine the degree of stenosis of the common carotid artery (CCA), the CCA bifurcation or the internal carotid artery (ICA). The blood frequencies of T-, B-, NK-cells, regulatory T cells (Treg), activated T-helpers (Th), IL10-producing Th, Th1 and Th17, as well as blood levels of hsCRP, sCD25, IL10 and IL17a were assessed. RESULTS: The frequencies of Th17 were increased in patients with ICA stenosis >35% and >50% vs. patients with ICA stenosis <35%. Th17 blood level ≥0.55 % of lymphocytes was associated with more severe stenosis of ICA (OR 4.3 (1.0-17.6), p < 0.05 for ICA stenosis of 35-50% and 6.8 (1.3-35.0), p < 0.05 for ICA stenosis >50%). BMI positively correlated with the CCA bifurcation stenosis degree (r = 0.33, p < 0.05). CONCLUSION: The severity of ICA stenosis can be associated with the circulating Th17 level.
RESUMEN
In a 2-year prospective study, prognostic significance of the blood content of IL-10-producing CD4+ T lymphocytes for progression of coronary artery atherosclerosis was assessed. Patients with verified stable angina (n=36) admitted for scheduled coronary angiography and coronary stenting were enrolled. The blood levels of CD4+FoxpP3+ Treg, CD4+IFNγ+ Th1, CD4+IL17+ Th17, CD4+IL10+ cells, sCD25, IL-10, IL-17, C-reactive protein, and lipoprotein (a) were assayed before endovascular interventions. The blood content of CD4+IL10+ T cells below 3.3% was associated with progression of coronary artery atherosclerosis (OR 12.0 (2.3, 61.0), sensitivity 77%, specificity 78%, p=0.003). No differences in other immunological parameters and common atherosclerosis risk factors in the groups were revealed. We hypothesize that the content of CD4+IL10+ T cells can be an important predictive marker for the progression of coronary atherosclerosis.
Asunto(s)
Angina Estable/sangre , Aterosclerosis/sangre , Enfermedad de la Arteria Coronaria/sangre , Interleucina-10/sangre , Linfocitos T Reguladores/inmunología , Anciano , Angina Estable/diagnóstico por imagen , Angina Estable/inmunología , Angina Estable/patología , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/inmunología , Aterosclerosis/patología , Biomarcadores/sangre , Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , Recuento de Linfocito CD4 , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/inmunología , Enfermedad de la Arteria Coronaria/patología , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-10/inmunología , Interleucina-17/sangre , Interleucina-17/inmunología , Lipoproteína(a)/sangre , Lipoproteína(a)/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Linfocitos T Reguladores/patología , Células TH1/inmunología , Células TH1/patología , Células Th17/inmunología , Células Th17/patologíaRESUMEN
Automated Fmoc solid-phase technique was used to synthesize Cys-containing linear peptide fragments of monocyte chemoattractant protein-1 and chemokine domain of fractalkine along with their analogues with Cys residue being either modified or replaced with Ser. Chimeric symmetric and asymmetric disulfides were also prepared from the former linear precursors. A SAR study on a set of the newly synthesized peptides revealed that capacity to stimulate migration of monocytes and to influence cell motility in vitro, in general, critically depends on the presence of Cys free thiol group in the molecule. Notably, all analogs lacking this feature, including chimeric disulfides, demonstrated lack of effect on monocyte migration.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Quimiocina CCL2 , Monocitos/metabolismo , Péptidos , Línea Celular Tumoral , Humanos , Monocitos/citología , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacologíaAsunto(s)
Quimiocina CCL2/química , Quimiocina CCL2/farmacología , Monocitos/fisiología , Cicatrización de Heridas/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Movimiento Celular/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Monocitos/efectos de los fármacos , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Ratas , Ratas WistarRESUMEN
During acute rejection of renal allografts C-reactive protein is excreted in urine in a monomeric form. We developed an immunochemical method for detecting monomeric C-reactive protein in human physiological fluids, which is based on latex agglutination.