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Interferon beta induces mature dendritic cell apoptosis through caspase-11/caspase-3 activation.

ABSTRACT: Although interferon beta (IFNbeta) decreases relapse rate and disease activity in multiple sclerosis (MS), the mechanisms involved have not been elucidated. The present study is the first report on the apoptotic effect of IFNbeta in mature, but not immature, myeloid dendritic cells (DCs). Both exogenous IFNbeta added to DCs matured through exposure to proinflammatory cytokines and endogenous IFNbeta secreted after lipopolysaccharide stimulation induced DC cell death. Apoptosis of mature DCs required both NF-kappaB and STAT-1 activation, and was mediated through the induction of caspase-11 expression and activation of caspase-3. In vivo, we observed increased caspase-11 expression and a significant decrease in the number of splenic DCs after lipopolysaccharide administration in wt but not in STAT-1-deficient mice. Since mature DCs are major contributors to the inflammatory response and essential partners in the induction of adaptive immunity, IFNbeta-dependent elimination of activated DCs could play an essential role in re-establishing homeostasis, and might represent a new molecular mechanism for the therapeutic effect of IFNbeta in MS.

SUBMITTER: Yen JH

PROVIDER: S-EPMC2727412 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Interferon beta induces mature dendritic cell apoptosis through caspase-11/caspase-3 activation.

Yen Jui-Hung JH Ganea Doina D

Blood 20090616 7

Although interferon beta (IFNbeta) decreases relapse rate and disease activity in multiple sclerosis (MS), the mechanisms involved have not been elucidated. The present study is the first report on the apoptotic effect of IFNbeta in mature, but not immature, myeloid dendritic cells (DCs). Both exogenous IFNbeta added to DCs matured through exposure to proinflammatory cytokines and endogenous IFNbeta secreted after lipopolysaccharide stimulation induced DC cell death. Apoptosis of mature DCs requ ...[more]

PMID: 19531658

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Project description:Recent researches have shown that estrogen receptor-β (ERβ) activator may be a potent anticancer agent for prostate cancer (PCa), and our previous study also indicated that dioscin can upregulate the expression of ERβ in MC3T3-E1 cell. In the present work, the activity and mechanism of dioscin, a natural product, against PCa were investigated. The results showed that dioscin markedly inhibited cell viability, colony formation, motility and induced apoptosis in PC3 cells. Moreover, dioscin disrupted the formation of PC3 cell-derived mammospheres and reduced aldehyde dehydrogenase (ALDH) level and the CD133+/CD44+ cells, indicating that dioscin had a potent inhibitory activity on prostate cancer stem cells (PCSCs). In vivo results also showed that dioscin significantly suppressed the tumor growth of PC3 cell xenografts in nude mice. Furthermore, mechanism investigation showed that dioscin markedly upregulated ERβ expression level, subsequently increased prolyl hydroxylase 2 level, decreased the levels of hypoxia-inducible factor-1α, vascular endothelial growth factor A and BMI-1, and thus induced cell apoptosis by regulating the expression levels of caspase-3 and Bcl-2 family proteins. In addition, transfection experiment of ERβ-siRNA further indicated that diosicn showed excellent activity against PCa in vitro and in vivo by increasing ERβ expression level. The co-immunoprecipitation (Co-IP) results further suggested that dioscin promoted the interaction of c-ABL and ERβ, but did not change c-ABL expression. Moreover, the molecular docking assay showed that dioscin processed powerful affinity toward to ERβ mainly through the strong hydrogen bonding and hydrophobic effects, and the actions of dioscin on ERβ activation and tumor cells inhibition were significantly weakened in the mutational (Phe-336, Phe-468) PC3 cells. Collectively, these findings proved that dioscin exerted efficient anti-PCa activity via activation of ERβ, which should be developed as an efficient candidate in clinical for treating this cancer in the future.

Project description:Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc(min) mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.

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Interferon beta induces mature dendritic cell apoptosis through caspase-11/caspase-3 activation.

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Interferon beta induces mature dendritic cell apoptosis through caspase-11/caspase-3 activation.

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