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
Increased concentration of lipoprotein(a) is a risk factor of coronary heart disease. lipoprotein(a) consists of LDL-like and highly polymorphic apolipoprotein(a). Here we studied the effect of lipoprotein(a)-containing sera with different apolipoprotein(a) phenotypes on lipid accumulation by THP-1 monocyte-like cells. Cholesterol concentration in lysates of THP-1 cells was significantly higher after their incubation with lipoprotein(a)-containing serum samples with low-molecular-weight phenotype of apolipoprotein(a) in comparison with samples with a high-molecular-weight apolipoprotein(a) phenotype irrespective of initial cholesterol level as well as serum concentrations of apoB-100, oxidized LDL, and circulating immune complexes. The presence of the most atherogenic small dense LDL subfractions in examined sera in addition to a low-molecular-weight apolipoprotein(a) phenotype resulted in significant elevation of cholesterol accumulation by THP-1 cells. The data obtained explain greater atherogenicity of lipoprotein(a) with low-molecular-weight apolipoprotein(a) phenotype.
Asunto(s)
Apolipoproteínas A/metabolismo , Colesterol/metabolismo , Apolipoproteínas/metabolismo , Medio de Cultivo Libre de Suero , Humanos , Macrófagos/metabolismo , Monocitos/metabolismo , Células THP-1RESUMEN
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
We developed a technology of labeling bone marrow precursor cells with the Lin-c-kit+ phenotype in culture by green fluorescent protein gene using a lentivirus vector. The proposed system provides effective transduction of bone marrow precursor cells and high transgene expression level in vitro (27%). The integration of the transgene into the transduced cell genome in vivo was verified by the method of splenic colonies.