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Myeloma cells and human umbilical vein endothelial cells (HUVECs) were co-cultured to model in vitro the interactions between myeloma and endothelium, and treated with thalidomide and two selective cytokine inhibitory drugs (SelCIDs, phosphodiesterase-4 inhibitors). Flow cytometry and enzyme-linked immunosorbent assay were used to assess production of two key cytokines – vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) – and apoptosis in co-cultured HUVECs and myeloma cells. VEGF was produced by both myeloma cells and HUVECs, while IL-6 was almost exclusively produced by endothelial cells. In co-culture, there was significant up-regulation of VEGF and IL-6 production compared with the sum of separate myeloma and endothelial cell cultures. SelCIDs markedly inhibited production of both cytokines in co-cultures, with CC-10004 being more potent than CC-1088. In addition, SelCIDs induced myeloma cell apoptosis. Apoptosis in co-cultured myeloma cells was significantly lower than in those cultured separately, suggesting that co-culture partially protected myeloma cells from drug-induced apoptosis. This protective effect was probably due to IL-6 produced by endothelial cells in co-culture as addition of anti-IL-6 neutralizing antibody, but not anti-VEGF antibody, abrogated it. In conclusion, SelCIDs can exert their anti-myeloma activity through two mechanisms, i.e. inhibition of VEGF and IL-6 production by interacting myeloma and endothelium and induction of myeloma cell apoptosis. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Mier-Cabrera J, Jiménez-Zamudio L, García-Latorre E, Cruz-Orozco O, Hernández-Guerrero C. Quantitative and qualitative peritoneal immune profiles, T-cell apoptosis and oxidative stress-associated characteristics in women with minimal and mild endometriosis. BJOG 2011;118:6-16. To assess immunological variables, T-cell apoptosis and oxidative stress markers in the peripheral blood and peritoneal fluid of women with (WEN) and without (WWE) endometriosis. Observational and transverse case-control study. National Institute of Perinatology, Mexico City, Mexico. Peripheral blood and peritoneal fluid obtained from 30 WWE and 32 WEN. Blood was drawn before surgery and peritoneal fluid was collected during surgery but before any surgical procedure had been carried out. Flow cytometry, spectrophotometry, high-performance liquid chromatography and multiplex immunoassay analyses were performed. Peripheral and peritoneal lymphocyte subpopulations (CD3, CD4 CD3, CD8 CD3, CD16 CD56, human leucocyte antigen-DR CD3 and CD19), intracellular CD4 CD3 and CD8 CD3 cytokine synthesis (interleukin-2 [IL-2] and interferon-γ [IFN-γ]), CD3 apoptosis, malondialdehyde and ascorbate concentrations and peritoneal cytokine concentrations. No differences were found in peripheral and peritoneal lymphocyte subsets between the groups. Peritoneal T lymphocytes from WEN produced less IL-2 and IFN-γ than those from WWE. Peritoneal malondialdehyde concentrations were higher and ascorbate concentrations were lower in WEN than in WWE. Higher peritoneal concentrations of pro-inflammatory cytokines (IL-1β, tumour necrosis factor-α and IL-6) and chemokines (IL-10, IL-8, eotaxin, vascular endothelial growth factor, monocyte chemotactic protein-1 and regulated upon activation, normal T-cell expressed, and secreted) and lower concentrations of IFN-γ, IL-1 receptor antagonist and IL-15 were found in WEN. No statistical differences were found in IL-2, IL-4, IL-12 and IL-13 concentrations. The alterations observed in WEN were associated with a diminished peritoneal T helper type 1 immune response. Pro-inflammatory, chemotactic, angiogenic and oxidative stress markers were altered in the peritoneal milieu of WEN. These changes appeared to contribute to the peritoneal immune alterations found. [ABSTRACT FROM AUTHOR]

Please cite this paper as: T-lymphocyte-induced, fas-mediated apoptosis is associated with early keratinocyte differentiation. Experimental Dermatology 2009. The development of eczematous lesions is thought to be due in part to a breakdown in skin barrier function as a result of T lymphocytes (T cells) invading the skin causing epidermal keratinocyte apoptosis. In this study, we investigated the interaction of T cells and keratinocytes on apoptosis and terminal differentiation using an in vitro co-culture system. Experiments were performed using the HaCaT keratinocyte cell line or normal human epidermal keratinocytes. Activated human peripheral blood-derived T cells were found to induce Fas-dependent keratinocyte apoptosis by up to sixfold. Increased Fas was associated with increased IFN-γ. The T-cell apoptotic signal was found to target preferentially keratinocytes in the very early stages of terminal differentiation, such as those with low levels of α6-integrin expression, and result in subsequent increased caspase 3 activity. This observation was accompanied by a marked increase in keratinocyte ICAM-1 expression and its ligand LFA-1 on T cells. Our data suggest that T cells may initiate the onset of keratinocyte terminal differentiation making them more susceptible to Fas-dependent cell death signals delivered by the T cells. [ABSTRACT FROM AUTHOR]

1. Telomeres (ends of chromosomes) undergo constant remodelling during cell development, proliferation and differentiation, as well as in neoplastic cell immortalization and transformation. How the cellular microenvironment influences telomere remodelling (lengthening or shortening) remains largely unknown. 2. Recently, studies from our laboratories and others have indicated that growth factors and cytokines have significant roles in regulating telomere remodelling and thus influence cell functions and properties. Cancer cells must maintain their already short telomeres either by the enzyme telomerase or, more rarely, through alternative lengthening of telomeres, which functions independently of cellular regulation. 3. However, application of transforming growth factor-β family cytokines induces transcriptional inhibition of telomerase in cancer cells, leading to telomere shortening, cell senescence (ageing) and apoptosis (death) by mechanisms dependent on telomerase inhibition. Furthermore, selective gene silencing of vascular endothelial growth factor and/or the telomerase catalytic subunit (i.e. telomerase reverse transcriptase) potently inhibits the growth of cervical cancer and laryngeal squamous cancer in mice. 4. The present paper summarizes our current understanding of the negative regulation by cytokines of telomere maintenance and thus cancer cell proliferation in cultured cells and mouse models. [ABSTRACT FROM AUTHOR]

Ceramide has been recognized as a common intracellular second messenger for various cytokines, growth factors and other stimuli, such as CD95, chemotherapeutic drugs and stress factors. To understand the role of ceramide during apoptosis and other cellular responses, it is critically important to characterize direct targets of ceramide action. In this paper, we show that ceramide specifically binds to and activates the endosomal acidic aspartate protease cathepsin D. Direct interaction of ceramide with cathepsin D results in autocatalytic proteolysis of the 52 kDa pre-pro cathepsin D to form the enzymatically active 48/32 kDa isoforms of cathepsin D. Add sphingomyelinase (A-SMase)-deficient cells show decreased cathepsin D activity, which could be reconstituted by transfection with A-SMase cDNA. The results of our study identify cathepsin D as the first endosomal ceramide target that colocalizes with and may mediate downstream signaling effects of A-SMase. [ABSTRACT FROM AUTHOR]

The article presents information on an abstract of the paper "Differential Responses of Oligodendrocytes to Tumor Necrosis Factor and Other Pro-Apoptotic Agents," which will be presented at the 30th meeting of the American Society for Neurochemistry. The meeting will be held from March 14-17, 1999 in New Orleans, Louisiana. According to the paper, despite the possibility of three death pathways, all cells with oligodendrocyte characteristics are protected from apoptosis.