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1.
Apoptosis ; 20(5): 671-8, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25637184

RESUMEN

It has become widely accepted that along with their ability to directly regulate gene expression, estrogens also influence cell signalling and cell function via rapid membrane-initiated events. Many of these signalling processes are dependent on estrogen receptors (ER) localized to the plasma membrane. However, the mechanisms by which ER are able to trigger cell signalling when targeted to the membrane surface have to be determined yet. Lipid rafts seem to be essential for the plasma membrane localization of ER and play a critical role in their membrane-initiated effects. In this review, we briefly recapitulate the localization and function of ER in different cell types and mostly discuss the possible role of lipid rafts in this context. Further studies in this field may disclose new promising therapeutic avenues by the disruption of lipid rafts in those diseases in which membrane ER activation has been demonstrated to play a pathogenetic role.


Asunto(s)
Estrógenos/fisiología , Homeostasis , Microdominios de Membrana/fisiología , Animales , Plaquetas/fisiología , Células Endoteliales/fisiología , Humanos , Linfocitos/fisiología , Músculo Liso Vascular/citología , Miocitos Cardíacos/fisiología , Miocitos del Músculo Liso/fisiología , Neuronas/fisiología , Transducción de Señal
2.
J Cell Physiol ; 229(12): 1990-8, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24777636

RESUMEN

Statins, widely used for treatment of hypercholesterolemia, have been demonstrated to exert pleiotropic beneficial effects independently of their cholesterol-lowering action, such as anti-inflammatory activity. A gender disparity has been observed in their cholesterol lowering activity as well as in response to these "off label" effects. Monocytes play a central role in atherosclerotic disease and, more in general, in inflammatory responses, through their chemotactic function and cytokine production. On these bases, in the present work, we examined the effect of statins on homeostasis and migration properties of freshly isolated monocytes from male and female healthy donors. Two prototypic natural and synthetic statins with different polarity, that is, type 1 and type 2 statins, have been considered: simvastatin and atorvastatin. Freshly isolated monocytes from peripheral blood of male and female healthy donors were treated with these drugs in the absence or presence of lipopolysaccharide (LPS) stimulation. Results obtained indicated that the polar statin efficiently inhibited chemotaxis of monocytes more than the apolar statin and that this effect was more significantly induced in cells from females than in cells from males. Dissecting the mechanisms involved, we found that these results could mainly be due to differential effects on: (i) the release of key cytokines, for example, MCP-1 and TNF-α; (ii) the maintenance of the redox homeostasis; (iii) a target activity on microfilament network integrity and function. All in all these results could suggest a reappraisal of "off-label" effects of statins taking into account either their chemical structure, that is, molecular polarity, or the gender issue.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Monocitos/efectos de los fármacos , Caracteres Sexuales , Aterosclerosis/patología , Atorvastatina , Movimiento Celular/efectos de los fármacos , Femenino , Voluntarios Sanos , Ácidos Heptanoicos/administración & dosificación , Humanos , Inflamación/genética , Inflamación/patología , Lipopolisacáridos/toxicidad , Masculino , Pirroles/administración & dosificación , Simvastatina/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismo
3.
Part Fibre Toxicol ; 11: 74, 2014 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-25498254

RESUMEN

BACKGROUND: Diesel exhaust particles (DEP) are major constituents of ambient air pollution and their adverse health effect is an area of intensive investigations. With respect to the immune system, DEP have attracted significant research attention as a factor that could influence allergic diseases interfering with cytokine production and chemokine expression. With this exception, scant data are available on the impact of DEP on lymphocyte homeostasis. Here, the effects of nanoparticles from Euro 4 (E4) and Euro 5 (E5) light duty diesel engines on the phenotype and function of T lymphocytes from healthy donors were evaluated. METHODS: T lymphocytes were isolated from peripheral blood obtained from healthy volunteers and subsequently stimulated with different concentration (from 0.15 to 60 µg/ml) and at different time points (from 24 h to 9 days) of either E4 or E5 particles. Immunological parameters, including apoptosis, autophagy, proliferation levels, mitochondrial function, expression of activation markers and cytokine production were evaluated by cellular and molecular analyses. RESULTS: DEP exposure caused a pronounced autophagic-lysosomal blockade, thus interfering with a key mechanism involved in the maintaining of T cell homeostasis. Moreover, DEP decreased mitochondrial membrane potential but, unexpectedly, this effect did not result in changes of the apoptosis and/or necrosis levels, as well as of intracellular content of adenosine triphosphate (ATP). Finally, a down-regulation of the expression of the alpha chain of the interleukin (IL)-2 receptor (i.e., the CD25 molecule) as well as an abnormal Th1 cytokine expression profile (i.e., a decrease of IL-2 and interferon (IFN)-γ production) were observed after DEP exposure. No differences between the two compounds were detected in all studied parameters. CONCLUSIONS: Overall, our data identify functional and phenotypic T lymphocyte parameters as relevant targets for DEP cytotoxicity, whose impairment could be detrimental, at least in the long run, for human health, favouring the development or the progression of diseases such as autoimmunity and cancer.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Regulación hacia Abajo/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-2/antagonistas & inhibidores , Activación de Linfocitos/efectos de los fármacos , Hollín/toxicidad , Linfocitos T/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Adulto , Contaminantes Atmosféricos/química , Contaminantes Atmosféricos/metabolismo , Autofagia/efectos de los fármacos , Transporte Biológico , Biomarcadores/metabolismo , Células Cultivadas , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Cinética , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Persona de Mediana Edad , Tamaño de la Partícula , Hollín/química , Hollín/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/ultraestructura , Emisiones de Vehículos/análisis , Adulto Joven
4.
FASEB J ; 26(4): 1400-12, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22247332

RESUMEN

Autophagy is a lysosome-mediated catabolic process that allows cells to degrade unwanted cytoplasmic constituents and to recycle nutrients. Autophagy is also involved in innate and adaptive immune responses, playing a key role in interactions against microbes, in antigen processing for major histocompatibility complex (MHC) presentation, and in lymphocyte development, survival, and proliferation. Over recent years, perturbations in autophagy have been implicated in a number of diseases, including autoimmunity. Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by autoimmune responses against self-antigens generated by dying cells. Genome-wide association studies have linked several single-nucleotide polymorphisms (SNPs) in the autophagy-related gene Atg5 to SLE susceptibility. Loss of Atg5-dependent effects, including clearance of dying cells and cell antigen presentation, might contribute to the autoimmunity and inflammation associated with SLE. Moreover, activation of the mammalian target of rapamycin (mTOR), a key player in the autophagy regulation, has recently been demonstrated in SLE, confirming an altered autophagy pathway in this disease. In the present review, we summarize the autophagy mechanisms, their molecular regulation, and their relevance in immunity and autoimmunity. The potential of targeting autophagy pathway in SLE, by developing innovative therapeutic approaches, has finally been discussed.


Asunto(s)
Inmunidad Adaptativa , Autoinmunidad/inmunología , Autofagia/inmunología , Inmunidad Innata , Lupus Eritematoso Sistémico/inmunología , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Linfocitos/inmunología , Fagocitos/inmunología
5.
FASEB J ; 26(11): 4722-32, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22835828

RESUMEN

Autophagy, the cytoprotection mechanism that takes place under metabolic impairment, has been implicated in the pathogenesis of autoimmunity. Here, we investigated the spontaneous and induced autophagic behavior of T lymphocytes from patients with systemic lupus erythematosus (SLE) compared with that of T lymphocytes from healthy donors by measuring the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II. No significant differences in spontaneous autophagy were found between T lymphocytes from patients with SLE and from healthy donors, apart from CD4(+) naive T cells from patients with SLE in which constitutively higher levels of autophagy (P<0.001) were detected. At variance, whereas treatment of T lymphocytes from healthy donors with serum IgG from patients with SLE resulted in a 2-fold increase in LC3-II levels (P<0.001), T lymphocytes from SLE patients were resistant to autophagic induction and also displayed an up-regulation of genes negatively regulating autophagy, e.g., α-synuclein. These findings could open new perspectives in the search for pathogenetic determinants of SLE progression and in the development of therapeutic strategies aimed to recover T-cell compartment homeostasis by restoring autophagic susceptibility.


Asunto(s)
Autofagia/fisiología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/fisiología , Adulto , Anciano , Autoanticuerpos , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Regulación de la Expresión Génica , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto Joven
6.
Arthritis Rheum ; 64(3): 778-87, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21968947

RESUMEN

OBJECTIVE: Estrogens influence many physiologic processes and are also implicated in the development or progression of numerous diseases, including autoimmune disorders. Aberrations of lymphocyte homeostasis that lead to the production of multiple pathogenic autoantibodies, including autoantibodies specific to estrogen receptor (ER), have been detected in the peripheral blood of patients with systemic lupus erythematosus (SLE). This study was undertaken to assess the presence of both anti-ERα and anti-ERß antibodies in sera from patients with SLE, to analyze the effect of these antibodies on peripheral blood T lymphocyte homeostasis, and to evaluate their role as determinants of disease pathogenesis and progression. METHODS: Anti-ER antibody serum immunoreactivity was analyzed by enzyme-linked immunosorbent assay in samples from 86 patients with SLE and 95 healthy donors. Phenotypic and functional analyses were performed by flow cytometry and Western blotting. RESULTS: Anti-ERα antibodies were present in 45% of the patients with SLE, whereas anti-ERß antibodies were undetectable. In healthy donors, anti-ERα antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes as well as proliferation of anti-CD3-stimulated T lymphocytes. A significant association between anti-ERα antibody values and clinical parameters, i.e., the SLE Disease Activity Index and arthritis, was found. CONCLUSION: Our data suggest that anti-ERα autoantibodies interfere with T lymphocyte homeostasis and are significantly associated with lupus disease activity.


Asunto(s)
Autoanticuerpos/inmunología , Receptor alfa de Estrógeno/inmunología , Homeostasis/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Síndrome de Behçet/sangre , Síndrome de Behçet/inmunología , Western Blotting , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Receptor beta de Estrógeno/inmunología , Femenino , Citometría de Flujo , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto Joven
7.
Clin Immunol ; 137(1): 122-33, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20580318

RESUMEN

We investigated in systemic sclerosis (SSc) patients the T cell homeostasis and its relationship with the clinical course of the disease. Distribution of peripheral T cell subsets, thymic output, lymphocyte proliferation and apoptosis were analyzed by flow cytometry or ELISA. Age inappropriate levels of naive CD4(+) T cells and thymic output were observed. Proliferation of CD4(+) T cells, lymphocyte apoptosis and CD4(+) regulatory T (Treg) cell frequency were significantly higher than those observed in controls and significantly correlated with clinical phenotypes and clinical progression parameters i.e., diffusing capacity of the lung for carbon monoxide (DLCO) and disease activity. These data indicate that the evaluation of the T cell homeostasis can represent a valuable prognostic tool for SSc patients and it is useful to distinguish between limited and diffuse phenotypes. A therapeutic intervention targeted at reversing T cell homeostasis abnormalities would therefore potentially be helpful in counteracting disease progression.


Asunto(s)
Homeostasis/inmunología , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/fisiopatología , Linfocitos T/inmunología , Linfocitos T/patología , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/inmunología , Apoptosis/inmunología , Recuento de Linfocito CD4 , Monóxido de Carbono/metabolismo , Proliferación Celular , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Intercambio Gaseoso Pulmonar/fisiología , Esclerodermia Difusa/sangre , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/inmunología , Esclerodermia Difusa/fisiopatología , Esclerodermia Limitada/sangre , Esclerodermia Limitada/diagnóstico , Esclerodermia Limitada/inmunología , Esclerodermia Limitada/fisiopatología , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/diagnóstico , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Adulto Joven
8.
FASEB J ; 23(4): 978-84, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19074513

RESUMEN

Cell death processes have been widely investigated in recent years in order to elucidate the different pathways involved in the complex machinery implicated in determining cell fate. Different forms of cell death have been described: Apart from the classical form of death known as necrosis, a well-characterized traumatic injury of the cell, several additional forms of cell death have been identified. Of these, apoptosis has been characterized in the greatest detail. Defects in the mechanisms of cell demise (that is, an excess of or decrease in apoptosis) have been associated with the pathogenesis of a number of human diseases. Here we review some new aspects derived from recent insights into this field, particularly the hypothesis that cells of males and females could display several different features, including those determining their fate.


Asunto(s)
Apoptosis/fisiología , Células/efectos de los fármacos , Hormonas Gonadales/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Muerte Celular/fisiología , Línea Celular , Línea Celular Tumoral , Células/patología , Femenino , Células Germinativas , Hormonas Gonadales/fisiología , Humanos , Masculino , Modelos Biológicos , Necrosis , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Factores Sexuales
9.
Cells ; 8(7)2019 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-31331091

RESUMEN

Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ERα Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ERα Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ERα is embedded, restored tamoxifen sensitivity, preventing anti-ERα Abs effects. In conclusion, detection of serum anti-ERα Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients.


Asunto(s)
Antineoplásicos Hormonales/inmunología , Autoanticuerpos/sangre , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/inmunología , Receptor alfa de Estrógeno/inmunología , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos Hormonales/uso terapéutico , Femenino , Humanos , Células MCF-7 , Ratones , Ratones SCID , Persona de Mediana Edad , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Int Arch Allergy Immunol ; 145(3): 258-67, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-17921676

RESUMEN

BACKGROUND: Evans syndrome (ES) is a rare disorder characterized by combined autoimmune thrombocytopenia and autoimmune hemolytic anemia. Several studies have documented a number of B cell defects, whereas only limited information is currently available about the T cell subset. METHODS: A wide panel of immunological analyses aiming specifically at a quantitative and qualitative evaluation of the T cell compartment was performed in an unusual case of ES. The peripheral distribution of the T cell subsets, the diversity of the T cell receptor (TCR) repertoires, the cytokine profile and the T cell apoptosis have been longitudinally evaluated. RESULTS: On first investigation, flow-cytometric immunophenotyping showed a remarkable alteration of T cell homeostasis with deeply reduced CD4+ naive T cells and recent thymic emigrants. This was seen in association with increased levels of T cell activation and apoptosis. Consistently with these data the cytokine profile was characterized by high interferon-gamma and low interleukin-2 levels. Staining for CD4 and CD25 molecules showed decreased percentages of circulating regulatory T cells according to the autoimmune nature of ES. Finally, restricted TCR repertoires were demonstrated by a skewed TCR beta chain variable (TCRBV) gene usage as well as oligoclonal third complementarity-determining region (CDR3) profiles. A deterioration of the above-mentioned parameters and a worsening of the clinical condition were observed during the follow-up requiring more intensive treatments. CONCLUSION: The demonstration of multiple T cell defects, in addition to providing pathogenetic information, is likely to alter both acute treatment and outcome of ES.


Asunto(s)
Anemia Hemolítica Autoinmune/inmunología , Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos T/fisiología , Trombocitopenia/inmunología , Adolescente , Apoptosis , Antígenos CD4/análisis , Antígenos CD4/metabolismo , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Regiones Determinantes de Complementariedad/análisis , Citometría de Flujo , Humanos , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/análisis , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Estudios Longitudinales , Activación de Linfocitos , Masculino , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Subgrupos de Linfocitos T/patología , Subgrupos de Linfocitos T/ultraestructura , Timo/inmunología
11.
Front Immunol ; 9: 1903, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30174672

RESUMEN

Estrogens, in particular 17ß-estradiol (E2), have a strong influence on the immune system and also affect pathological conditions such as autoimmune diseases. The biological effects of E2 are mediated by two intracellular receptors, i.e., estrogen receptor (ER)α and ERß, which function as ligand-activated nuclear transcription factors producing genomic effects. Immune cells express both ERα and ERß that play a complex role in modulating inflammation. Phytoestrogens display estrogen-like effects. Among them, silibinin, the major active constituent of silymarin extracted by the milk thistle (Silybum marianum), has been suggested to have an ERß selective binding. Silibinin is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects; however, the role of silibinin in modulating human immune responses and its impact on autoimmunity remains unclear. Aim of this study was to dissect the ability of the ERß natural ligand silibinin to modulate T cell immunity, taking into account possible differences between females and males, and to define its possible role as therapeutic tool in immune-mediated diseases. To this purpose, female and age-matched male healthy subjects and patients with active rheumatoid arthritis (RA) were recruited. We evaluated the ability of silibinin to modulate ERß expression in T lymphocytes and its effects on T cell functions (i.e., apoptosis, proliferation, and cytokine production). We also analyzed whether silibinin was able to modulate the expression of microRNA-155 (miR-155), which strongly contributes to the pathogenesis of RA driving aberrant activation of the immune system. We demonstrated that silibinin upregulated ERß expression, induced apoptosis, inhibited proliferation, and reduced expression of the pro-inflammatory cytokines IL-17 and TNF-α, through ERß binding, in T lymphocytes from female and male healthy donors. We obtained similar results in T lymphocytes from patients with active RA in term of apoptosis, proliferation, and cytokine production. In addition, we found that silibinin acted as an epigenetic modifier, down-modulating the expression of miR-155. In conclusion, our data demonstrated an immunosuppressive role of silibinin, supporting its application in the treatment of autoimmune diseases as drug, but also as dietary nutritional supplement, opening new perspective in the field of autoimmune disease management.


Asunto(s)
Artritis Reumatoide/etiología , Artritis Reumatoide/metabolismo , Receptor beta de Estrógeno/agonistas , Inmunomodulación/efectos de los fármacos , Inmunosupresores/farmacología , Silibina/farmacología , Anciano , Apoptosis/efectos de los fármacos , Artritis Reumatoide/patología , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunidad , Inmunosupresores/uso terapéutico , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , MicroARNs/genética , Persona de Mediana Edad , Silibina/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/metabolismo
12.
Oncotarget ; 8(5): 8522-8535, 2017 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-28052027

RESUMEN

Although Hodgkin lymphoma (HL) is curable with current therapy, at least 20% of patients relapse or fail to make complete remission. In addition, patients who achieve long-term disease-free survival frequently undergo infertility, secondary malignancies, and cardiac failure, which are related to chemotherapeutic agents and radiation therapies. Hence, new therapeutic strategies able to counteract the HL disease in this important patient population are still a matter of study. Estrogens, in particular 17ß-estradiol (E2), have been suggested to play a role in lymphoma cell homeostasis by estrogen receptors (ER) ß activation. On these bases, we investigated whether the ligation of ERß by a selective agonist, the 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. We found that DPN-mediated ERß activation led to a reduction of in vitro cell proliferation and cell cycle progression by inducing autophagy. In nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells, ERß activation by DPN was able to reduce lymphoma growth up to 60% and this associated with the induction of tumor cell autophagy. Molecular characterization of ERß-induced autophagy revealed an overexpression of damage-regulated autophagy modulator 2 (DRAM2) molecule, whose role in autophagy modulation is still debated. After ERß activation, both DRAM2 and protein 1 light chain 3 (LC3), a key actor in the autophagosome formation, strictly interacted each other and localized at mitochondrial level.Altogether these results suggest that targeting ERß with selective agonists might affect HL cell proliferation and tumor growth via a mechanism that brings into play DRAM2-dependent autophagic cascade.


Asunto(s)
Autofagia/efectos de los fármacos , Receptor beta de Estrógeno/agonistas , Enfermedad de Hodgkin/tratamiento farmacológico , Nitrilos/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Humanos , Ligandos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Proteínas Asociadas a Microtúbulos/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Ann Ist Super Sanita ; 52(2): 205-12, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27364395

RESUMEN

Autoimmune diseases are characterized by an exaggerated immune response leading to damage and dysfunction of specific or multiple organs and tissues. Most autoimmune diseases are more prevalent in women than in men. Symptom severity, disease course, response to therapy and overall survival may also differ between males and females with autoimmune diseases. Sex hormones have a crucial role in this sex bias, with estrogens being potent stimulators of autoimmunity and androgens playing a protective role. Accumulating evidence indicates that genetic, epigenetic and environmental factors may also contribute to sex-related differences in risk and clinical course of autoimmune diseases. In this review, we discuss possible mechanisms for sex specific differences in autoimmunity with a special focus on three paradigmatic diseases: systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.


Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/fisiopatología , Caracteres Sexuales , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/microbiología , Femenino , Hormonas Esteroides Gonadales , Humanos , Masculino , Microbiota , Factores Sexuales
14.
Oncoimmunology ; 5(2): e1074375, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27057440

RESUMEN

Estrogen receptors have recently been demonstrated at the cell surface. Unlike nuclear receptors, they are able to trigger rapid responses inside the cells. In this study, we evaluated the presence and the possible role of autoantibodies specific to estrogen receptor (anti-ER Abs) in the peripheral blood of breast cancer patients. Anti-ERα Abs were detectable in 22/48 (46%) patients' sera and their levels positively correlated with the percentage of Ki-67-positive breast cancer cells. Anti-ERα Abs purified from breast cancer patients' sera were able: (i) to recognize ERα epitopes expressed at the cell surface of ER-positive breast cancer cells, (ii) to trigger rapid extracellular signal-regulated kinase (ERK) phosphorylation, and (iii) to induce cell proliferation. Our results suggest that anti-ERα Abs can act as estrogen agonists playing a pathogenetic role as breast cancer-promoting factors. These autoantibodies could also be considered as possible peripheral blood biomarkers indicative of the breast cancer growth potential.

15.
Biol Sex Differ ; 7: 3, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26759713

RESUMEN

BACKGROUND: Current evidence indicates that estrogens, in particular 17ß-estradiol (E2), play a crucial role in the gender bias of autoimmune diseases although the underlying molecular mechanisms have not yet been fully elucidated. Immune cells have estrogen receptors (ERs), i.e., ERα and ERß, that play pro- and anti-inflammatory functions, respectively, and the presence of one estrogen receptor (ER) subtype over the other might change estrogen effects, promoting or dampening inflammation. In this study, we contributed to define the influences of E2 on T cells from female patients with systemic lupus erythematosus (SLE), a representative autoimmune disease characterized by a higher prevalence in women than in men (female/male ratio 9:1). Particularly, our aim was to evaluate whether alterations of ERα and ERß expression in T cells from female SLE patients may impact lymphocyte sensitivity to E2 and anti-ERα antibody (anti-ERα Ab) stimulation interfering with cell signaling and display a direct clinical effect. METHODS: Sixty-one premenopausal female patients with SLE and 40 age-matched healthy donors were recruited. Patients were divided into two groups based on the SLE Disease Activity Index 2000 (SLEDAI-2K) (i.e., <6 and ≥6). ER expression was evaluated in T lymphocytes by flow cytometry, immunofluorescence, and Western blot analyses. Serum anti-ERα Ab levels were analyzed by enzyme-linked immunosorbent assay (ELISA). ER-dependent signaling pathways were measured by a phosphoprotein detection kit. RESULTS: Intracellular ERß expression was significantly lower in T cells from patients with SLEDAI-2K ≥6 as compared with healthy donors and patients with SLEDAI-2K <6 and negatively correlated with disease activity. The expression of intracellular and membrane-associated-ERα was similar in SLE and control T cells. ER-dependent signaling pathways were activated in T cells from SLE patients with SLEDAI-2K ≥6, but not with SLEDAI-2K <6, when both membrane and intracellular ERs were stimulated by co-treatment with E2 and anti-ERα Abs. CONCLUSIONS: Our results demonstrate an altered ER profile in SLE patients, possibly contributing to SLE pathogenesis and interfering with clinical activity, and highlight the potential exploitation of T cell-associated ERß as a biomarker of disease activity.

16.
Oncotarget ; 6(38): 40443-51, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26497217

RESUMEN

Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)ß expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = 27) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-α therapy and responsive to treatment, ERß expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERß expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERß expression inversely correlated with interleukin (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERß downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERß as a biomarker of endoscopic disease activity.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Proliferación Celular/efectos de los fármacos , Receptor beta de Estrógeno/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Adulto , Anciano , Western Blotting , Células CACO-2 , Estudios de Casos y Controles , Colon/citología , Colon/efectos de los fármacos , Colon/metabolismo , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto Joven
17.
Antioxid Redox Signal ; 21(1): 103-22, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24359147

RESUMEN

SIGNIFICANCE: The signaling function of redox molecules is essential for an efficient and proper execution of a large number of cellular processes, contributing to the maintenance of cell homeostasis. Excessive oxidative stress is considered as playing an important role in the pathogenesis of autoimmune diseases by enhancing inflammation and breaking down the immunological tolerance through protein structural modifications that induce the appearance of neo/cryptic epitopes. RECENT ADVANCES: There is a complex reciprocal relationship between oxidative stress and both apoptosis and autophagy, which is essential to determine cell fate. This is especially relevant in the context of autoimmune disorders in which apoptosis and autophagy play a crucial pathogenic role. CRITICAL ISSUES: In this review, we describe the latest developments with regard to the involvement of redox molecules in the initiation and progression of autoimmune disorders, focusing on their role in cell fate regulation. We also discuss new therapeutic approaches that target oxidative stress in the treatment of these disorders. The administration of antioxidants is scarcely studied in autoimmunity, and future analyses are needed to assess its beneficial effects in preventing or ameliorating these diseases. FUTURE DIRECTIONS: Deciphering the intricate relationships between oxidative stress and both apoptosis and autophagy in the context of autoimmunity could be critical in elucidating key pathogenic mechanisms and could lead to novel interventions for the clinical management of autoimmune diseases.


Asunto(s)
Autoinmunidad/fisiología , Autofagia/inmunología , Animales , Apoptosis/genética , Apoptosis/fisiología , Autofagia/fisiología , Humanos , Oxidación-Reducción , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo
18.
PLoS One ; 8(9): e74332, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24058548

RESUMEN

Systemic sclerosis (SSc) is a multisystem autoimmune disease of unknown etiology characterized by inflammation, autoantibody production, and fibrosis. It predominantly affects women, this suggesting that female sex hormones such as estrogens may play a role in disease pathogenesis. However, up to date, the role of estrogens in SSc has been scarcely explored. The activity of estrogens is mediated either by transcription activity of the intracellular estrogen receptors (ER), ERα and ERß, or by membrane-associated ER. Since the presence of autoantibodies to ERα and their role as estrogen agonists interfering with T lymphocyte homeostasis were demonstrated in other autoimmune diseases, we wanted to ascertain whether anti-ERα antibodies were detectable in sera from patients with SSc. We detected anti-ERα antibody serum immunoreactivity in 42% of patients with SSc (30 out of 71 analyzed). Importantly, a significant association was found between anti-ERα antibody values and key clinical parameters of disease activity and severity. Fittingly, anti-ERα antibody levels were also significantly associated with alterations of immunological features of SSc patients, including increased T cell apoptotic susceptibility and changes in T regulatory cells (Treg) homeostasis. In particular, the percentage of activated Treg (CD4(+)CD45RA(-) FoxP3(bright)CD25(bright)) was significantly higher in anti-ERα antibody positive patients than in anti-ERα antibody negative patients. Taken together our data clearly indicate that anti-ERα antibodies, probably via the involvement of membrane-associated ER, can represent: i) promising markers for SSc progression but, also, ii) functional modulators of the SSc patients' immune system.


Asunto(s)
Autoanticuerpos/sangre , Progresión de la Enfermedad , Receptor alfa de Estrógeno/inmunología , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/patología , Adulto , Anciano , Autoanticuerpos/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Demografía , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/sangre , Adulto Joven
19.
Immunol Lett ; 132(1-2): 79-85, 2010 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-20542061

RESUMEN

Estrogens are well-known regulators of the immune responses. Most of their effects are mediated by two receptors: estrogen receptor (ER)alpha and ERbeta. Up to date the presence of intracellular ER in human immune cells represents a controversial issue, while their surface membrane expression has scarcely been explored. In this study we investigated the intracellular and cell surface expression of ERalpha and ERbeta in human peripheral blood lymphocytes (PBL) by flow and static cytometry as well as by Western Blot. To this aim we used five different commercial antibodies recognizing distinct ER epitopes. We observed that CD4(+) and CD8(+) T lymphocytes, B lymphocytes and NK cells contain intracellular ERalpha and ERbeta, being the ERalpha46 isoform the most represented ER. However, significant differences could be observed among the antibodies studied in terms of immunoreactivity and specificity. Importantly, we also found a cell surface expression of ERalpha46 isoform. We also observed that a membrane-impermeant form of E2 induced a rapid phosphorylation of extracellular signal-regulated kinase (ERK), a significant proliferation of T lymphocytes, and IFN-gamma production by NK cells, thus suggesting the expression of a functional mERalpha. In conclusion our data could provide new insights as concerns the estrogen-related mechanisms of immune system modulation. They also suggest the need for a reappraisal of the experimental conditions for the characterization of the ER expression.


Asunto(s)
Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Linfocitos/metabolismo , Adulto , Anciano , Linfocitos B/metabolismo , Western Blotting , Membrana Celular/metabolismo , Células Cultivadas , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Estrógenos/metabolismo , Citometría de Flujo , Humanos , Células Asesinas Naturales/metabolismo , Masculino , Persona de Mediana Edad , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Subgrupos de Linfocitos T/metabolismo , Adulto Joven
20.
FEBS J ; 276(20): 5920-35, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19740103

RESUMEN

In the present study, we investigated the mechanisms of the resistance to CD95-mediated cell death and the effects of interferon-gamma in modulating the susceptibility to CD95-induced apoptosis of human astroglioma cells. We found that interferon-gamma administration sensitized cancer cells to CD95-mediated apoptosis. The mechanism underlying this sensitization appeared to be associated with a framework of cell changes, including up-regulation of death receptor at the cell surface, pro-apoptotic molecule Bax and Bak over-expression and mitochondria hyperpolarization, as is known to be associated with cell sensitization to apoptosis. An involvement of the proteasome activity in the mechanism of sensitization by interferon-gamma was also detected, probably as a result of the differing expression of catalytic proteasome subunits. Taken together, these findings suggest that interferon-gamma could represent a promising candidate for modulating astroglioma cell apoptotic susceptibility.


Asunto(s)
Apoptosis/efectos de los fármacos , Astrocitoma/metabolismo , Interferón gamma/farmacología , Receptor fas/metabolismo , Antivirales/farmacología , Astrocitoma/tratamiento farmacológico , Western Blotting , Caspasa 10/metabolismo , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Fragmentación del ADN/efectos de los fármacos , Citometría de Flujo , Humanos , Interferón gamma/ultraestructura , Microscopía , Microscopía Electrónica de Transmisión , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo
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