RESUMO
The Fas/FasL system plays a central role in the physiological regulation of apoptosis and has been implicated in the pathogenesis of several neoplasms and diseases of the immune system. Until now, it has received little attention in the context of ageing, but there is sufficient evidence that it plays an important role in this process and its deregulation favours the development of age-related diseases such as osteoarthritis, diabetes, eye diseases, ischaemic processes, anaemia, Alzheimer's disease and cancer. With this in mind, the aim of this work was to describe the main changes that occur in the Fas/FasL system during ageing and their association with the development of age-related diseases. Furthermore, it discusses how exercise and diet, considered the cornerstone of almost all healthy ageing programmes, produce beneficial effects through the regulation of the Fas/FasL system.
Assuntos
Neoplasias , Receptor fas , Humanos , Receptor fas/fisiologia , Proteína Ligante Fas , Envelhecimento , ApoptoseRESUMO
Earlier studies from our laboratory demonstrated that acute experimental Trypanosoma cruzi infection promotes an intense inflammation along with a sepsis-like dysregulated adrenal response characterized by normal levels of ACTH with raised glucocorticoid secretion. Inflammation was also known to result in adrenal cell apoptosis, which in turn may influence HPA axis uncoupling. To explore factors and pathways which may be involved in the apoptosis of adrenal cells, together with its impact on the functionality of the gland, we carried out a series of studies in mice lacking death receptors, such as TNF-R1 (C57BL/6-Tnfrsf1a tm1Imx or TNF-R1-/-) or Fas ligand (C57BL/6 Fas-deficient lpr mice), undergoing acute T. cruzi infection. Here we demonstrate that the late hypercorticosterolism seen in C57BL/6 mice during acute T. cruzi infection coexists with and hyperplasia and hypertrophy of zona fasciculata, paralleled by increased number of apoptotic cells. Apoptosis seems to be mediated mainly by the type II pathway of Fas-mediated apoptosis, which engages the mitochondrial pathway of apoptosis triggering the cytochrome c release to increase caspase-3 activation. Fas-induced apoptosis of adrenocortical cells is also related with an exacerbated production of intra-adrenal cytokines that probably maintain the late supply of adrenal hormones during host response. Present results shed light on the molecular mechanisms dealing with these phenomena which are crucial not only for the development of interventions attempting to avoid adrenal dysfunction, but also for its wide occurrence in other infectious-based critical illnesses.
Assuntos
Córtex Suprarrenal/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Receptor fas/fisiologia , Córtex Suprarrenal/microbiologia , Animais , Apoptose/imunologia , Apoptose/fisiologia , Caspase 3/metabolismo , Citocinas/metabolismo , Proteína Ligante Fas/metabolismo , Proteína Ligante Fas/fisiologia , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/metabolismo , Receptor fas/metabolismoRESUMO
Fas ligation via the ligand FasL activates the caspase-8/caspase-3-dependent extrinsic death pathway. In so-called type II cells, an additional mechanism involving tBid-mediated caspase-9 activation is required to efficiently trigger cell death. Other pathways linking FasL-Fas interaction to activation of the intrinsic cell death pathway remain unknown. However, ATP release and subsequent activation of purinergic P2X(7) receptors (P2X(7)Rs) favors cell death in some cells. Here, we evaluated the possibility that ATP release downstream of caspase-8 via pannexin1 hemichannels (Panx1 HCs) and subsequent activation of P2X(7)Rs participate in FasL-stimulated cell death. Indeed, upon FasL stimulation, ATP was released from Jurkat cells in a time- and caspase-8-dependent manner. Fas and Panx1 HCs colocalized and inhibition of the latter, but not connexin hemichannels, reduced FasL-induced ATP release. Extracellular apyrase, which hydrolyzes ATP, reduced FasL-induced death. Also, oxidized-ATP or Brilliant Blue G, two P2X(7)R blockers, reduced FasL-induced caspase-9 activation and cell death. These results represent the first evidence indicating that the two death receptors, Fas and P2X(7)R connect functionally via caspase-8 and Panx1 HC-mediated ATP release to promote caspase-9/caspase-3-dependent cell death in lymphoid cells. Thus, a hitherto unsuspected route was uncovered connecting the extrinsic to the intrinsic pathway to amplify death signals emanating from the Fas receptor in type II cells.
Assuntos
Trifosfato de Adenosina/fisiologia , Apoptose , Caspase 8/fisiologia , Proteína Ligante Fas/fisiologia , Receptores Purinérgicos P2X7/fisiologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Apirase/fisiologia , Caspase 3/fisiologia , Caspase 9/fisiologia , Conexinas/fisiologia , Humanos , Células Jurkat , Proteínas do Tecido Nervoso/fisiologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Corantes de Rosanilina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptor fas/fisiologiaRESUMO
We have previously reported that Fas activation induces apoptosis of anterior pituitary cells from rats at proestrus but not at diestrus and in an estrogen-dependent manner. In this study, we evaluated the effect of Fas activation on apoptosis of lactotropes and somatotropes during the estrous cycle and explored the action of gonadal steroids on Fas-induced apoptosis. Also, we studied whether changes in Fas expression are involved in the apoptotic response of anterior pituitary cells. Fas activation increased the percentage of TUNEL-positive lactotropes and somatotropes at proestrus but not at diestrus. FasL triggered apoptosis of somatotropes only when cells from ovariectomized rats were cultured in the presence of 17 ß-estradiol (E2). Progesterone (P4) blocked the apoptotic action of the Fas/FasL system in lactotropes and somatotropes incubated with E2. Both E2 and P4 increased the percentage of cells expressing Fas at the cell membrane. Our results show that Fas activation induces apoptosis of lactotropes and somatotropes at proestrus but not at diestrus. Gonadal steroids may be involved in the apoptotic response of lactotropes and somatotropes, suggesting that Fas activation is implicated in the renewal of these pituitary subpopulations during the estrous cycle. The effect of gonadal steroids on Fas expression may be only partially involved in regulation of the Fas/FasL apoptotic pathway in the anterior pituitary gland.
Assuntos
Apoptose/efeitos dos fármacos , Hormônios Esteroides Gonadais/farmacologia , Lactotrofos/citologia , Somatotrofos/citologia , Receptor fas/fisiologia , Animais , Apoptose/fisiologia , Células Cultivadas , Estradiol/farmacologia , Ciclo Estral , Proteína Ligante Fas/fisiologia , Feminino , Expressão Gênica/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Lactotrofos/efeitos dos fármacos , Ovariectomia , Adeno-Hipófise/citologia , Progesterona/farmacologia , Ratos , Ratos Wistar , Somatotrofos/efeitos dos fármacos , Receptor fas/genéticaRESUMO
The elucidation of the intricate molecular network of costimulus and regulatory pathways of the immune system led to the design of molecular therapies that specifically inactivate some cellular responses and ameliorate some autoimmune and inflammatory diseases. This innovative concept opens a new class of therapies, and one of the central components that could be targeted in future molecular therapies is the Fas-based pathway. Both soluble and membrane-bound Fas and Fas-L molecules exert a wide range of proinflammatory functions through the secretion of cytokines and chemokines, cellular chemotaxis, transcriptional regulation, cellular death, and others. Accordingly, many chronic inflammatory diseases, including myocarditis, are attenuated in mice lacking either molecule. Although it is tempting to speculate that the Fas/Fas-L pathway could be targeted for in vivo myocarditis therapy, the plurality of Fas/Fas-L functions can be an obstacle, leading to important side effects. In this review, we suggest that the injection of nonagonistic antibodies raised against the Fas molecule or the inactivation of downstream Fas-1,4,5-inositol triphosphate cascade are possible targets for myocarditis treatment.
Assuntos
Proteína Ligante Fas/fisiologia , Miocardite/terapia , Receptor fas/fisiologia , Animais , Anticorpos/uso terapêutico , Apoptose/fisiologia , Proteína Ligante Fas/imunologia , Miocardite/imunologia , Miocardite/metabolismoRESUMO
Microorganisms with pathogen-associated molecular patterns (PAMP) activate B cells directly by binding to TLR and also indirectly by inducing APC to release cytokines such as BAFF that promote B cell survival. We found that murine B cells activated concomitantly with LPS (TLR-4 ligand) and BAFF are protected from spontaneous apoptosis, but are more susceptible to Fas/CD95-mediated cell death. This increased susceptibility to Fas-induced apoptosis is associated with a dramatic coordinated up-regulation of Fas/CD95 and IRF-4 expression through a mechanism mediated, at least in part, by inhibition of the MEK/ERK pathway. Up-regulation of Fas/CD95 by BAFF is restricted to B cells activated through TLR-4, but not through TLR-9, BCR or CD40. TLR ligands differ in the BAFF family receptors (R) they induce on B cells: BAFF-R is increased by the TLR4 ligand, LPS, but not by the TLR9 ligand, CpG-containing oligodeoxynucleotides, which, in contrast, strongly up-regulates transmembrane activator and CAML interactor (TACI). This suggests the up-regulation of Fas by BAFF is mediated by BAFF-R and not by TACI. Consistently, APRIL, which binds to TACI and B cell maturation antigen but not BAFF-R, did not enhance Fas expression on LPS-activated B cells. Increased susceptibility to Fas-mediated killing of B cells activated with LPS and BAFF may be a fail-safe mechanism to avoid overexpansion of nonspecific or autoreactive B cells.
Assuntos
Apoptose/imunologia , Fator Ativador de Células B/fisiologia , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Lipopolissacarídeos/farmacologia , Receptor fas/fisiologia , Animais , Subpopulações de Linfócitos B/metabolismo , Morte Celular/imunologia , Células Cultivadas , Inibidores do Crescimento/biossíntese , Inibidores do Crescimento/fisiologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Regulação para Cima/imunologia , Receptor fas/biossínteseRESUMO
Apoptosis is a morphologically defined form of programmed cell death (PCD) that is mediated by the activation of members of the caspase family. Analysis of death-receptor signaling in lymphocytes has revealed that caspase-dependent signaling pathways are also linked to cell death by nonapoptotic mechanisms, indicating that apoptosis is not the only form of PCD. Under physiological and pathological conditions, cells demonstrate a high degree of flexibility in cell-death responses, as is reflected in the existence of a variety of mechanisms, including necrosis-like PCD, autophagy (or type II PCD), and accidental necrosis. In this review, we discuss recent data suggesting that canonical apoptotic pathways, including death-receptor signaling, control caspase-dependent and -independent cell-death pathways.
Assuntos
Apoptose , Animais , Autofagia , Caspases/fisiologia , Ceramidas/metabolismo , Ativação Enzimática , Humanos , Receptores do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais , Receptor fas/fisiologiaRESUMO
The ability of a microorganism to elicit or evade B cell responses represents a determinant factor for the final outcome of an infection. Although pathogens may subvert humoral responses at different stages of B cell development, most studies addressing the impact of an infection on the B cell compartment have focused on mature B cells within peripheral lymphoid organs. Herein, we report that a protozoan infection, i.e. a Trypanosoma cruzi infection, induces a marked loss of immature B cells in the BM, which also compromises recently emigrated B cells in the periphery. The depletion of BM immature B cells is associated with an increased rate of apoptosis mediated by a parasite-indirect mechanism in a Fas/FasL-independent fashion. Finally, we demonstrated that myeloid cells play an important role in B cell depletion, since CD11b(+) BM cells from infected mice secrete a product of the cyclooxygenase pathway that eliminates immature B cells. These results highlight a previously unrecognized maneuver used by a protozoan parasite to disable B cell generation, limiting host defense and favoring its chronic establishment.
Assuntos
Linfócitos B/imunologia , Doença de Chagas/imunologia , Células Mieloides/fisiologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Animais , Apoptose , Proteína Ligante Fas , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Prostaglandinas/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Receptor fas/fisiologiaRESUMO
In the acute phase of Trypanosoma cruzi infection there is a prominent thymus atrophy, which is determined by massive loss of immature CD4/CD8 double positive cells. Recently, the involvement of a parasite transialidase, which is shed from the parasite cell membrane and the activation of P2X(7), a purinergic receptor, were stated as important pathways leading to thymus atrophy. In this work we evaluated the possible involvement of Fas- and perforin-based cytotoxic pathways in the thymus atrophy induced by T. cruzi infection using gld/gld and perforin (-/-) mice. We found similar kinetics of thymus atrophy in mice competent or deficient in both cytotoxic pathways, indicating that both molecules are not directly involved in the thymus atrophy, either inducing cellular death or as co-stimulatory molecules.
Assuntos
Doença de Chagas/patologia , Glicoproteínas de Membrana/fisiologia , Timo/patologia , Receptor fas/fisiologia , Animais , Atrofia , Doença de Chagas/imunologia , Modelos Animais de Doenças , Proteína Ligante Fas , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Perforina , Proteínas Citotóxicas Formadoras de Poros , Timo/imunologiaRESUMO
The control of B cell expansion has been thought to be solely regulated by T lymphocytes. We show in this study that Trypanosoma cruzi infection induces up-regulation of both Fas and Fas ligand (FasL) molecules on B cells and renders them susceptible to B cell-B cell killing (referred to as fratricide throughout this paper) mediated via Fas/FasL. Moreover, by in vivo administration of anti-FasL blocking mAb we demonstrate that Fas-mediated B cell apoptosis is an ongoing process during this parasitic infection. We also provide evidence that B cells that have switched to IgG isotype are the preferential targets of B cell fratricide. More strikingly, this death pathway selectively affects IgG(+) B cells reactive to parasite but not self Ags. Parasite-specific but not self-reactive B cells triggered during this response are rescued after either in vitro or in vivo FasL blockade. Fratricide among parasite-specific IgG(+) B lymphocytes could impair the immune control of T. cruzi and possibly other chronic protozoan parasites. Our results raise the possibility that the blockade of Fas/FasL interaction in the B cell compartment of T. cruzi-infected mice may provide a means for enhancing antiparasitic humoral immune response without affecting host tolerance.