RESUMO
Apoptosis is implicated in the generation and resolution of inflammation in response to bacterial pathogens. All bacterial pathogens produce lipoproteins (BLPs), which trigger the innate immune response. BLPs were found to induce apoptosis in THP-1 monocytic cells through human Toll-like receptor-2 (hTLR2). BLPs also initiated apoptosis in an epithelial cell line transfected with hTLR2. In addition, BLPs stimulated nuclear factor-kappaB, a transcriptional activator of multiple host defense genes, and activated the respiratory burst through hTLR2. Thus, hTLR2 is a molecular link between microbial products, apoptosis, and host defense mechanisms.
Assuntos
Apoptose , Proteínas de Bactérias/farmacologia , Proteínas de Drosophila , Lipoproteínas/farmacologia , Glicoproteínas de Membrana/metabolismo , Monócitos/citologia , Receptores de Superfície Celular/metabolismo , Anticorpos Monoclonais , Proteínas de Bactérias/metabolismo , Linhagem Celular/metabolismo , Cicloeximida/farmacologia , Citotoxicidade Imunológica , Genes Reporter , Humanos , Receptores de Lipopolissacarídeos/análise , Lipopolissacarídeos/imunologia , Lipoproteínas/metabolismo , Glicoproteínas de Membrana/imunologia , Monócitos/imunologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/imunologia , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia , Receptor 2 Toll-Like , Receptores Toll-Like , Transfecção , Células Tumorais CultivadasRESUMO
In the past few years, there has been remarkable progress unraveling the mechanism and significance of eukaryotic programmed cell death (PCD), or apoptosis. Not surprisingly, it has been discovered that numerous, unrelated microbial pathogens engage or circumvent the host's apoptotic program. In this chapter, we briefly summarize apoptosis, emphasizing those studies which assist the reader in understanding the subsequent discussion on PCD and pathogens. We then examine the relationship between virulent bacteria and apoptosis. This section is organized to reflect both common and diverse mechanisms employed by bacteria to induce PCD. A short discussion of parasites and fungi is followed by a detailed description of the interaction of viral pathogens with the apoptotic machinery. Throughout the review, apoptosis is considered within the broader contexts of pathogenesis, virulence, and host defense. Our goals are to update the reader on this rapidly expanding field and identify topics in the current literature which demand further investigation.
Assuntos
Apoptose/fisiologia , Animais , Fenômenos Fisiológicos Bacterianos , Fungos/fisiologia , Humanos , Parasitos/fisiologiaRESUMO
The innate immune system coordinates the inflammatory response to pathogens. To do so, cells of the innate immune system must rapidly discriminate between self and non-self. All bacteria express membrane-associated lipoproteins. These molecules activate cells of the innate immune system to initiate host defense mechanisms. However, it is currently unknown how the innate immune system recognizes bacterial lipoproteins. Here, we describe that in response to bacterial lipoprotein, human Toll-like receptor-2 activates three different cellular responses: nuclear factor-kappaB dependent transcription, programmed cell death and reactive oxygen species production. We propose that Toll-like receptor-2 fulfils multiple roles in the genesis of the immune response to bacterial pathogens.
Assuntos
Apoptose/fisiologia , Proteínas de Drosophila , Glicoproteínas de Membrana/fisiologia , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/fisiologia , Transdução de Sinais/fisiologia , Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Proteínas de Bactérias/farmacologia , Linhagem Celular , Humanos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Lipoproteínas/farmacologia , Glicoproteínas de Membrana/imunologia , NF-kappa B/biossíntese , Receptores de Superfície Celular/imunologia , Explosão Respiratória/imunologia , Receptor 2 Toll-Like , Receptores Toll-LikeRESUMO
Shigella spp. cause dysentery, a severe form of bloody diarrhea. Apoptosis, or programmed cell death, is induced during Shigella infections and has been proposed to be a key event in the pathogenesis of dysentery. Here, we describe a novel cytotoxic activity in the sterile-culture supernatants of Shigella flexneri. An identical activity was identified in purified S. flexneri endotoxin, defined here as a mixture of lipopolysaccharide (LPS) and endotoxin-associated proteins (EP). Separation of endotoxin into EP and LPS revealed the activity to partition exclusively to the EP fraction. Biochemical characterization of S. flexneri EP and culture supernatants, including enzymatic deactivation, reverse-phase high-pressure liquid chromatography analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and a Toll-like receptor-2 (TLR2) activation assay, indicates that the cytotoxic component is a mixture of bacterial lipoproteins (BLP). We show that biologically active BLP are liberated into culture supernatants of actively growing S. flexneri. In addition, our data indicate that BLP, and not LPS, are the component of endotoxin of gram-negative organisms responsible for activating TLR2. The activation of apoptosis by BLP shed from S. flexneri is discussed as a novel aspect of the interaction of bacteria with the host.
Assuntos
Apoptose , Proteínas de Bactérias/metabolismo , Proteínas de Drosophila , Lipoproteínas/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Shigella flexneri/metabolismo , Proteínas de Bactérias/biossíntese , Linhagem Celular , Fracionamento Químico , Cromatografia Líquida de Alta Pressão/métodos , Meios de Cultura , Humanos , Metabolismo dos Lipídeos , Lipopolissacarídeos/farmacologia , Lipoproteínas/biossíntese , Fenol/farmacologia , Toxina Shiga/farmacologia , Shigella flexneri/crescimento & desenvolvimento , Transdução de Sinais , Receptor 2 Toll-Like , Receptores Toll-Like , Ácido Tricloroacético/farmacologiaRESUMO
Macrophages can kill target cells independent of conventional immune specificity. Based on a re-examination of literature three decades old and recent experiments, Antonios Aliprantis and colleagues propose that macrophages kill target cells by inducing apoptosis. For this purpose, macrophages employ a selection of pro-apoptotic mediators including reactive oxygen and nitrogen species and tumour necrosis factor alpha.
Assuntos
Apoptose/imunologia , Citotoxicidade Imunológica/imunologia , Macrófagos/imunologia , Animais , HumanosRESUMO
The innate immune system uses Toll family receptors to signal for the presence of microbes and initiate host defense. Bacterial lipoproteins (BLPs), which are expressed by all bacteria, are potent activators of Toll-like receptor-2 (TLR2). Here we show that the adaptor molecule, myeloid differentiation factor 88 (MyD88), mediates both apoptosis and nuclear factor-kappaB (NF-kappaB) activation by BLP-stimulated TLR2. Inhibition of the NF-kappaB pathway downstream of MyD88 potentiates apoptosis, indicating that these two pathways bifurcate at the level of MyD88. TLR2 signals for apoptosis through MyD88 via a pathway involving Fas-associated death domain protein (FADD) and caspase 8. Moreover, MyD88 binds FADD and is sufficient to induce apoptosis. These data indicate that TLR2 is a novel 'death receptor' that engages the apoptotic machinery without a conventional cytoplasmic death domain. Through TLR2, BLP induces the synthesis of the precursor of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). Interestingly, BLP also activates caspase 1 through TLR2, resulting in proteolysis and secretion of mature IL-1beta. These results indicate that caspase activation is an innate immune response to microbial pathogens, culminating in apoptosis and cytokine production.
Assuntos
Apoptose/fisiologia , Proteínas de Arabidopsis , Proteínas de Drosophila , Glicoproteínas de Membrana/fisiologia , Receptores de Superfície Celular/fisiologia , Receptores Imunológicos , Transdução de Sinais/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Antígenos de Diferenciação/metabolismo , Antígenos de Diferenciação/fisiologia , Caspase 1/metabolismo , Caspase 8 , Caspase 9 , Caspases/metabolismo , Linhagem Celular , Ativação Enzimática , Ácidos Graxos Dessaturases/metabolismo , Humanos , Fator 88 de Diferenciação Mieloide , NF-kappa B/metabolismo , Ligação Proteica , Receptor 2 Toll-Like , Receptores Toll-LikeRESUMO
Shigella flexneri, an etiological agent of bacillary dysentery, causes apoptosis in vitro. Here we show that it also induces apoptosis in vivo. We were able to quantify the number of apoptotic cells in rabbit Peyer's patches infected with S. flexneri by detecting cells with fragmented DNA. Infection with virulent S. flexneri results in massive numbers of apoptotic cells within the lymphoid follicles. In contrast, neither an avirulent strain nor an avirulent strain capable of colonizing Peyer's patches increases the background level of apoptotic cells. Macrophages, T cells, and B cells are shown to undergo apoptosis in vivo. These results indicate that apoptosis may play a crucial role in the pathogenesis of shigellosis.