RESUMEN
The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.
Asunto(s)
Actinas , Neoplasias , ADN , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Citosol/metabolismo , Transducción de SeñalRESUMEN
Selective evolutionary pressure shapes the processes and genes that enable cancer survival and expansion in a tumour-suppressive environment. A distinguishing lethal feature of malignant cancer is its dissemination and seeding of metastatic foci. A key requirement for this process is the acquisition of a migratory/invasive ability. However, how the migratory phenotype is selected for during the natural evolution of cancer and what advantage, if any, it might provide to the growing malignant cells remain open issues. In this opinion piece, we discuss three possible answers to these issues. We will examine lines of evidence from mathematical modelling of cancer evolution that indicate that migration is an intrinsic selectable property of malignant cells that directly impacts on growth dynamics and cancer geometry. Second, we will argue that migratory phenotypes can emerge as an adaptive response to unfavourable growth conditions and endow cells not only with the ability to move/invade, but also with specific metastatic traits, including drug resistance, self-renewal and survival. Finally, we will discuss the possibility that migratory phenotypes are coincidental events that emerge by happenstance in the natural evolution of cancer. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.
Asunto(s)
Evolución Biológica , Carcinogénesis/metabolismo , Movimiento Celular/genética , Neoplasias/metabolismo , Selección Genética , Humanos , FenotipoRESUMEN
During wound repair, branching morphogenesis and carcinoma dissemination, cellular rearrangements are fostered by a solid-to-liquid transition, known as unjamming. The biomolecular machinery behind unjamming and its pathophysiological relevance remain, however, unclear. Here, we study unjamming in a variety of normal and tumorigenic epithelial two-dimensional (2D) and 3D collectives. Biologically, the increased level of the small GTPase RAB5A sparks unjamming by promoting non-clathrin-dependent internalization of epidermal growth factor receptor that leads to hyperactivation of the kinase ERK1/2 and phosphorylation of the actin nucleator WAVE2. This cascade triggers collective motility effects with striking biophysical consequences. Specifically, unjamming in tumour spheroids is accompanied by persistent and coordinated rotations that progressively remodel the extracellular matrix, while simultaneously fluidizing cells at the periphery. This concurrent action results in collective invasion, supporting the concept that the endo-ERK1/2 pathway is a physicochemical switch to initiate collective invasion and dissemination of otherwise jammed carcinoma.
Asunto(s)
Diferenciación Celular , Movimiento Celular , Línea Celular Tumoral , Proliferación Celular , Receptores ErbB/metabolismo , Humanos , Cinética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas de Unión al GTP rab5/metabolismoRESUMEN
Cell monolayers provide an interesting example of active matter, exhibiting a phase transition from flowing to jammed states as they age. Here we report experiments and numerical simulations illustrating how a jammed cellular layer rapidly reverts to a flowing state after a wound. Quantitative comparison between experiments and simulations shows that cells change their self-propulsion and alignment strength so that the system crosses a phase transition line, which we characterize by finite-size scaling in an active particle model. This wound-induced unjamming transition is found to occur generically in epithelial, endothelial and cancer cells.
Asunto(s)
Movimiento Celular , Modelos Biológicos , Células HeLa , HumanosRESUMEN
The originally published version of this Article contained an error in the name of the author Salvatore Corallino, which was incorrectly given as Corallino Salvatore. This has now been corrected in both the PDF and HTML versions of the Article.
RESUMEN
How cells move chemotactically remains a major unmet challenge in cell biology. Emerging evidence indicates that for interpreting noisy, shallow gradients of soluble cues a system must behave as an excitable process. Here, through an RNAi-based, high-content screening approach, we identify RAB35 as necessary for the formation of growth factors (GFs)-induced waves of circular dorsal ruffles (CDRs), apically restricted actin-rich migratory protrusions. RAB35 is sufficient to induce recurrent and polarized CDRs that travel as propagating waves, thus behaving as an excitable system that can be biased to control cell steering. Consistently, RAB35 is essential for promoting directed chemotactic migration and chemoinvasion of various cells in response to gradients of motogenic GFs. Molecularly, RAB35 does so by directly regulating the activity of p85/PI3K polarity axis. We propose that RAB35 is a molecular determinant for the control of an excitable, oscillatory system that acts as a steering wheel for GF-mediated chemotaxis and chemoinvasion.
Asunto(s)
Quimiotaxis/genética , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Células Epiteliales/metabolismo , Fibroblastos/metabolismo , Proteínas de Unión al GTP rab/genética , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestructura , Animales , Línea Celular Tumoral , Quimiotaxis/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/ultraestructura , Fibroblastos/efectos de los fármacos , Fibroblastos/ultraestructura , Expresión Génica , Células HeLa , Humanos , Ratones , Imagen Molecular , Factor de Crecimiento Derivado de Plaquetas/farmacología , Cultivo Primario de Células , Transducción de Señal , Proteínas de Unión al GTP rab/metabolismoRESUMEN
Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination.
Asunto(s)
Endocitosis , Epitelio/metabolismo , Fenómenos Biomecánicos , Línea Celular Tumoral , Membrana Celular/metabolismo , Humanos , Proteínas de Unión al GTP rab5/metabolismoRESUMEN
Dense monolayers of living cells display intriguing relaxation dynamics, reminiscent of soft and glassy materials close to the jamming transition, and migrate collectively when space is available, as in wound healing or in cancer invasion. Here we show that collective cell migration occurs in bursts that are similar to those recorded in the propagation of cracks, fluid fronts in porous media, and ferromagnetic domain walls. In analogy with these systems, the distribution of activity bursts displays scaling laws that are universal in different cell types and for cells moving on different substrates. The main features of the invasion dynamics are quantitatively captured by a model of interacting active particles moving in a disordered landscape. Our results illustrate that collective motion of living cells is analogous to the corresponding dynamics in driven, but inanimate, systems.
Asunto(s)
Movimiento Celular , Animales , Antígenos CD/metabolismo , Fenómenos Biomecánicos , Cadherinas/metabolismo , Bovinos , Línea Celular , Movimiento Celular/efectos de los fármacos , Colágeno/farmacología , Simulación por Computador , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Modelos Biológicos , Imagen de Lapso de TiempoRESUMEN
The role of endocytic proteins and the molecular mechanisms underlying epithelial cell cohesion and tumor dissemination are not well understood. Here, we report that the endocytic F-BAR-containing CDC42-interacting protein 4 (CIP4) is required for ERBB2- and TGF-ß1-induced cell scattering, breast cancer (BC) cell motility and invasion into 3D matrices, and conversion from ductal breast carcinoma in situ to invasive carcinoma in mouse xenograft models. CIP4 promotes the formation of an E-cadherin-CIP4-SRC complex that controls SRC activation, E-cadherin endocytosis, and localized phosphorylation of the myosin light chain kinase, thereby impinging on the actomyosin contractility required to generate tangential forces to break cell-cell junctions. CIP4 is upregulated in ERBB2-positive human BC, correlates with increased distant metastasis, and is an independent predictor of poor disease outcome in subsets of BC patients. Thus, it critically controls cell-cell cohesion and is required for the acquisition of an invasive phenotype in breast tumors.
Asunto(s)
Células Epiteliales/citología , Regulación Neoplásica de la Expresión Génica , Proteínas Asociadas a Microtúbulos/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Actomiosina/metabolismo , Animales , Cadherinas/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Línea Celular Tumoral , Endocitosis , Femenino , Humanos , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Antígenos de Histocompatibilidad Menor , Trasplante de Neoplasias , Receptor ErbB-2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The mechanisms by which tumor cells metastasize and the role of endocytic proteins in this process are not well understood. We report that overexpression of the GTPase RAB5A, a master regulator of endocytosis, is predictive of aggressive behavior and metastatic ability in human breast cancers. RAB5A is necessary and sufficient to promote local invasion and distant dissemination of various mammary and nonmammary tumor cell lines, and this prometastatic behavior is associated with increased intratumoral cell motility. Specifically, RAB5A is necessary for the formation of invadosomes, membrane protrusions specialized in extracellular matrix (ECM) degradation. RAB5A promotes RAB4- and RABENOSYN-5-dependent endo/exocytic cycles (EECs) of critical cargos (membrane-type 1 matrix metalloprotease [MT1-MMP] and ß3 integrin) required for invadosome formation in response to motogenic stimuli. This trafficking circuitry is necessary for spatially localized hepatocyte growth factor (HGF)/MET signaling that drives invasive, proteolysis-dependent chemotaxis in vitro and for conversion of ductal carcinoma in situ to invasive ductal carcinoma in vivo. Thus, RAB5A/RAB4 EECs promote tumor dissemination by controlling a proteolytic, mesenchymal invasive program.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas de Unión al GTP rab5/genética , Proteínas de Unión al GTP rab5/fisiología , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Matriz Extracelular/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Invasividad Neoplásica/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Proteolisis , Trasplante Heterólogo , Proteínas de Unión al GTP rab5/metabolismoRESUMEN
The multimolecular WAVE regulatory (WRC) and Arp2/3 complexes are primarily responsible to generate pushing forces at migratory leading edges by promoting branch elongation of actin filaments. The architectural complexity of these units betrays the necessity to impose a tight control on their activity. This is exerted through temporally coordinated and coincident signals which limit the intensity and duration of this activity. In addition, interactions of the WRC and Arp2/3 complexes with membrane binding and surprisingly membrane trafficking proteins is also emerging, revealing the existence of an 'endocytic wiring system' that spatially restrict branched actin elongation for the execution of polarized functions during cell migration.
Asunto(s)
Membrana Celular/metabolismo , Movimiento Celular , Seudópodos/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Actinas/metabolismo , Animales , HumanosRESUMEN
OBJECTIVES: The positive effects of spa therapy on ear, nose, and throat pathology are known but robust literature in this field, is still lacking. The aim of this study was to assess through a retrospective analysis, the effects on otitis media with effusion of Politzer endotympanic inhalation of sulphurous waters in children aged 5-9 years. METHODS: A cohort of 95 patients was treated with Politzer insufflations of sulphurous water: 58 patients did a cycle consisting of a treatment of 12 days per year for three consecutive years; 37 patients followed the same procedure for 5 years consecutively. The control population was represented by untreated, age-matched children. A standard audiometric test was used before and after each cycle of treatment. RESULTS: One cycle of Politzer inhalation of sulphur-rich water improved the symptoms. Three cycles definitively stabilized the improvement of hearing function. CONCLUSION: Our results show that otitis media with effusion in children can be resolved by an appropriate non-pharmacological treatment of middle ear with sulphur-rich water.
RESUMEN
The effects of exogenous hydrogen sulfide (H2S) on normal skin-derived immortalized human keratinocytes have been investigated in detail. We show in vitro that exogenous hydrogen sulfide reduces clonal growth, cell proliferation and cell adhesion of human keratinocytes. H(2)S, in fact, decreases the frequency of the putative keratinocyte stem cell subpopulation in culture, consequently affecting clonal growth, and impairs cell proliferation and adhesion of mature cells. As a mechanistic explanation of these effects, we show at the molecular level that (i) H2S reduces the Raf/MAPK kinase/ERK signaling pathway; (ii) the reduced adhesion of sulfur-treated cells is associated to the downregulation of the expression of beta4, alpha2 and alpha6 integrins that are necessary to promote cell adhesion as well as anti-apoptotic and proliferative signaling in normal keratinocytes. One specific interest of the effects of sulfurs on keratinocytes derives from the potential applications of the results, as sulfur is able to penetrate the skin and a sulfur-rich balneotherapy has been known for long to be effective in the treatment of psoriasis. Thus, the relevance of our findings to the pathophysiology of psoriasis was tested in vivo by treating psoriatic lesions with sulfurs at a concentration comparable to that most commonly found in sulfurous natural springs. In agreement with the in vitro observations, the immunohistochemical analysis of patient biopsies showed a specific downregulation of ERK activation levels, the key molecular event in the sulfur-induced effects on keratinocytes.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Sulfuro de Hidrógeno/toxicidad , Queratinocitos/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Anciano , Apoptosis/efectos de los fármacos , Bromodesoxiuridina/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular Transformada , Núcleo Celular/efectos de los fármacos , Núcleo Celular/enzimología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Citoplasma/efectos de los fármacos , Citoplasma/enzimología , Citometría de Flujo , Humanos , Sulfuro de Hidrógeno/uso terapéutico , Queratinocitos/metabolismo , Queratinocitos/patología , Masculino , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Psoriasis/enzimología , Psoriasis/patologíaRESUMEN
Fragile histidine triad (FHIT) is a tumor suppressor gene whose allelic loss is associated to a number of human cancers. FHIT protein acts as a diadenosine oligophosphate hydrolase, but its tumor suppressive activity appears as independent from its enzymatic activity. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in the FHIT-negative non-small lung cancer cell line Calu-1. We generated four FHIT-inducible Calu-1 cell clones and demonstrated that FHIT expression was able to protect cells from TRAIL-induced apoptosis, without affecting TRAIL-receptors surface expression. FHIT-specific small interference RNA transfection of SV40-immortalized normal bronchial BEAS cells that show levels of FHIT protein comparable to those of normal bronchial cells, resulted in a significant increase of TRAIL-induced apoptosis. Of note, suramin-mediated inhibition of FHIT enzymatic activity also enhanced TRAIL-induced apoptosis. We conclude that FHIT expression in lung cancer cells is protective from TRAIL-induced apoptosis. Our data suggest that FHIT exerts this protective effect downstream TRAIL-receptors and likely requires its dinucleoside-triphosphate hydrolase activity. As TRAIL represents in the near future a good candidate for death ligands-based anticancer therapy, its potential therapeutic use should be envisaged as preliminary to molecular genetics interventions or drug-induced epigenetic modulations aimed to restoring FHIT gene expression levels in non-small cells lung tumors.
Asunto(s)
Ácido Anhídrido Hidrolasas/metabolismo , Apoptosis/fisiología , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ácido Anhídrido Hidrolasas/genética , Línea Celular Tumoral , Ecdisterona/análogos & derivados , Ecdisterona/metabolismo , Células Epiteliales/citología , Células Epiteliales/fisiología , Humanos , Proteínas de Neoplasias/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
Despite the relevant therapeutic progresses made in these last 2 decades, the prognosis of acute myeloid leukemia (AML) remains poor. Phorbol esters are used at very low concentrations as differentiating agents in the therapy of myeloid leukemias. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in turn, is a death ligand that spares normal cells and is therefore currently under clinical trials for cancer therapy. Emerging evidence, however, suggests that TRAIL is also involved in nonapoptotic functions, like cell differentiation. PKCepsilon is differentially modulated along normal hematopoiesis, and its levels modulate the response of hematopoietic precursors to TRAIL. Here, we investigated the effects of the combination of phorbol esters (phorbol ester 4-beta-phorbol-12,13-dibutyrate [PDBu]) and TRAIL in the survival/differentiation of AML cells. We demonstrate here that PDBu sensitizes primary AML cells to both the apoptogenic and the differentiative effects of TRAIL via PKCepsilon down-modulation, without affecting TRAIL receptor surface expression. We believe that the use of TRAIL in combination with phorbol esters (or possibly more specific PKCepsilon down-modulators) might represent a significative improvement of our therapeutic arsenal against AML.
Asunto(s)
Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Ésteres del Forbol/farmacología , Proteína Quinasa C-epsilon/genética , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Técnicas de Cultivo de Célula , Diferenciación Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Células K562 , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Forbol 12,13-Dibutirato/administración & dosificación , Forbol 12,13-Dibutirato/farmacología , Ésteres del Forbol/administración & dosificación , Proteína Quinasa C-epsilon/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/administración & dosificación , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Células Tumorales CultivadasRESUMEN
The B203.13 monoclonal antibody was developed by immunizing mice with the B/monocyte biphenotypic cell line B1b. During normal hematopoiesis B203.13 is expressed on a fraction of CD34+ cells, while on mature cells it is only present on B-lymphocytes. We tested this antibody as a marker of childhood B-acute lymphoblastic leukemia (B-ALL). Bone marrow aspirates from 139 cases of early B-ALL and 25 controls were studied. About 40% of the B-ALL patients expressed B203.13. In these patients, B203.13 was constantly co-expressed with CD10, but never co-expressed with CD20, contrary to the controls. The CD10(+)/B203.13(+) phenotype was specific to B-ALL, since CD10(+)/CD20(+) cells from common acute lymphoblastic leukemia (c-ALL) did not express B203.13. We concluded that the use of B203.13 in association with CD10 and CD20 provides meaningful information for distinguishing normal residual B-cells from leukemic B-lymphoblasts and that recurrence of a CD10(+)/B203.13(+) phenotype after transplantation may be a very early relapse indicator of early B-acute lymphoblastic leukemia.
Asunto(s)
Antígenos de Neoplasias/biosíntesis , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Adolescente , Adulto , Antígenos CD20/biosíntesis , Antígenos CD20/inmunología , Niño , Preescolar , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Lactante , Masculino , Neprilisina/biosíntesis , Neprilisina/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunologíaRESUMEN
Protein kinase C (PKC)-mediated intracellular signaling participates in several key steps of hematopoietic cell differentiation. The epsilon isoform of PKC has been associated with erythroid differentiation as well as with the early phases of megakaryocytic (MK) lineage commitment. Here, we worked on the hypothesis that PKCepsilon expression levels might be modulated during MK differentiation, with a specific role in the early as well as in the late phases of thrombopoiesis. We demonstrate that--at variance with the erythroid lineage development--PKCepsilon is completely downmodulated in TPO-induced CD34 cells from day 6 onward. The forced expression of PKCepsilon in the late phases of MK differentiation delays the phenotypic differentiation of progenitors likely via Bcl-xL upregulation. Moreover, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), known as a negative regulator of early erythroid expansion, is not apoptogenic for thrombopoietin-induced CD34 cells, but rather accelerates their maturation. However, PKCepsilon levels negatively interfere also with the effects of TRAIL in MK differentiation. PKCepsilon can therefore be considered a signaling intermediate whose expression levels are finely tuned, with a virtually opposite kinetic, in erythroid versus megakaryocytic lineages, to adequately respond to the signaling requirements of the specific hematopoietic lineage.
Asunto(s)
Antígenos CD34/metabolismo , Diferenciación Celular/genética , Megacariocitos/citología , Proteína Quinasa C-epsilon/genética , Proteína Quinasa C-epsilon/fisiología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Regulación de la Expresión Génica/fisiología , Hematopoyesis/efectos de los fármacos , Hematopoyesis/genética , Humanos , Megacariocitos/efectos de los fármacos , Megacariocitos/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Trombopoyetina/farmacología , Factores de Tiempo , Proteína bcl-X/genéticaRESUMEN
The toxic effects of exogenous hydrogen sulfide on peripheral blood lymphocytes have been investigated in detail. Hydrogen sulfide is now considered as a gasotransmitter with specific functional roles in different cell types, like neurons and vascular smooth muscle. Here we show that exogenous hydrogen sulfide induces a caspase-independent cell death of peripheral blood lymphocytes that depends on their intracellular glutathione levels, with a physiologically relevant subset specificity for CD8+ T cells and NK cells. Although lymphocyte activation does not modify their sensitivity to HS-, after 24 h exposure to hydrogen sulfide surviving lymphocyte subsets show a dramatically decreased proliferation in response to mitogens and a reduced IL-2 production. Overall, our data demonstrate that HS- reduces the cellular cytotoxic response of peripheral blood lymphocytes as well as their production of IL-2, therefore de-activating the major players of local inflammatory responses, adding new basic knowledge to the clinically well known anti-inflammatory effects of sulfur compounds.