In recent years, researchers have showed a growing interest in the mechanistic relationship betwe... more In recent years, researchers have showed a growing interest in the mechanistic relationship between bone marrow adipose tissue and adjacent tumors. However, the impact of bone marrow adipocytes on development of hematological malignancies, particularly multiple myeloma is unknown. With aging, bone marrow changes occur and fatty deposits can occupy up to 70% of the BM cavity. Interactions of bone marrow adipose tissue with bone cells and other immune cells, possibly suggest indirect ways in which bone marrow adipocytes may affect MM disease progression. Leptin, an adipokine released by adipocytes and crucial in energy homeostasis, displays immune modulatory properties but its role in anti-tumor immunity remains unclear. In this study we aimed to investigate the intriguing relationship between leptin receptor activation and invariant natural killer T (iNKT) cell mediated anti-tumor immunity in multiple myeloma. The murine immunocompetent 5T33MM model, mimicking the human disease close...
Interleukin 5 (IL-5) is the key cytokine in an eosinophil&amp... more Interleukin 5 (IL-5) is the key cytokine in an eosinophil's life span: it supports eosinophilopoiesis and eosinophil differentiation, contributes to eosinophil migration, tissue localisation and function, and prevents eosinophil apoptosis. Given the likely role of eosinophils in chronic inflammatory diseases, a lot of research over the past decade was aimed at antagonising IL-5 function. It appears from recent studies that, although this can easily be achieved in vitro, blocking IL-5 function in vivo is much more difficult than originally anticipated. Here, we review the current status of IL-5 and IL-5 receptor research, with emphasis on strategies to interfere with IL-5 function.
After its discovery in 1994, it soon became clear that leptin acts as an adipocyte-derived hormon... more After its discovery in 1994, it soon became clear that leptin acts as an adipocyte-derived hormone with a central role in the control of body weight and energy homeostasis. However, a growing body of evidence has revealed that leptin is a pleiotropic cytokine with activities on many peripheral cell types. Inappropriate leptin signaling can promote autoimmunity, certain cardiovascular diseases, elevated blood pressure and cancer, which makes leptin and the leptin receptor interesting targets for antagonism. Profound insights in the leptin receptor (LR) activation mechanisms are a prerequisite for the rational design of these antagonists. In this review, we focus on the molecular mechanisms underlying leptin receptor activation and signaling. We also discuss the current strategies to interfere with leptin signaling and their therapeutic potential.
Hemangioblastomas express erythropoietin and the patients often present with polycythemia. Serum ... more Hemangioblastomas express erythropoietin and the patients often present with polycythemia. Serum erythropoietin was measured using a commercial immunoassay, a functional erythropoietin assay and iso-electric focusing. Despite the polycythemia, serum erythropoietin remained low, while a functional erythropoietin-assay showed a 4-5 higher activity in serum compared to the immunoassay. Iso-electric focusing of serum erythropoietin indicated overrepresentation of highly sialylated erythropoietin isoforms produced by the tumor. As a result, altered affinity of the monoclonal antibody used in the immunoassay for the hypersialylated isoforms was suggested. Analysis of erythropoietin isoforms may be helpful in distinguishing the ectopic erythropoietin isoforms from normally glycosylated erythropoietin.
We have designed a sensitive and versatile bioassay for quantification of series of cytokines. Th... more We have designed a sensitive and versatile bioassay for quantification of series of cytokines. The assay makes use of chimeric receptors composed of the extracellular, ligand-binding part of the cognate cytokine receptor and the transmembrane and cytosolic part of the type I interferon receptor. Receptors can be homo- (e.g. erythropoietin), di- (e.g. interleukin-5), or even trimeric (e.g. interleukin-2). Stable expression of these chimeras in the 2fTGH cell line allows an interferon-type signaling, which makes a positive selection in conditioned medium possible or a negative selection using a toxic guanine analog. The cytokine of interest is quantified by the extent of cell survival or cell toxicity respectively, which can be measured by easy and cheap crystal violet staining. This bioassay is sensitive in the lower picogram per milliliter range and, in contrast to ELISA methods, only measures the concentration of biologically active cytokines. Using this approach, hypersensitive 2fTGH cell lines have been developed for type I and II interferons, erythropoietin, interleukin-2, and interleukin-5.
Leptin plays a central role in the control of body weight and energy homeostasis, but is a pleiot... more Leptin plays a central role in the control of body weight and energy homeostasis, but is a pleiotropic cytokine with activities on many peripheral cell types. In this review, we discuss the interaction of leptin with its receptor, and focus on the structural and mechanistic aspects of the extracellular aspects of leptin receptor (LR) activation. We provide an extensive overview of all structural information that has been obtained for leptin and its receptor via X-ray crystallography, electron microscopy, small-angle X-ray scattering, homology modeling, and mutagenesis studies. The available knowledge is integrated into putative models toward a recapitulation of the LR activation mechanism.
Leptin is a multifunctional hormone produced by the ob gene and is secreted by adipocytes that re... more Leptin is a multifunctional hormone produced by the ob gene and is secreted by adipocytes that regulate food intake and energy metabolism. Numerous studies demonstrated that leptin is a novel neuroprotective effector, however, the mechanisms are largely unknown. Herein, we demonstrate the protective activities of leptin after ischemic stroke and provide the first evidence for the involvement of the connexin 43 (Cx43) in leptin-mediated neuroprotection. We found that leptin treatment reduces the infarct volume, improves animal behavioral parameters, and inhibits the elevation of Cx43 expression in vivo. In vitro, leptin reverses ischemia-induced SY5Y and U87 cells Cx43 elevation, secreted glutamate levels in medium and SY5Y cell death, these roles could be abolished by leptin receptor blocker. Additionally, leptin administration upregulated the extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation. Moreover, ERK1/2 inhibitors pretreatment reversed the effects of leptin on...
In recent years, researchers have showed a growing interest in the mechanistic relationship betwe... more In recent years, researchers have showed a growing interest in the mechanistic relationship between bone marrow adipose tissue and adjacent tumors. However, the impact of bone marrow adipocytes on development of hematological malignancies, particularly multiple myeloma is unknown. With aging, bone marrow changes occur and fatty deposits can occupy up to 70% of the BM cavity. Interactions of bone marrow adipose tissue with bone cells and other immune cells, possibly suggest indirect ways in which bone marrow adipocytes may affect MM disease progression. Leptin, an adipokine released by adipocytes and crucial in energy homeostasis, displays immune modulatory properties but its role in anti-tumor immunity remains unclear. In this study we aimed to investigate the intriguing relationship between leptin receptor activation and invariant natural killer T (iNKT) cell mediated anti-tumor immunity in multiple myeloma. The murine immunocompetent 5T33MM model, mimicking the human disease close...
Interleukin 5 (IL-5) is the key cytokine in an eosinophil&amp... more Interleukin 5 (IL-5) is the key cytokine in an eosinophil's life span: it supports eosinophilopoiesis and eosinophil differentiation, contributes to eosinophil migration, tissue localisation and function, and prevents eosinophil apoptosis. Given the likely role of eosinophils in chronic inflammatory diseases, a lot of research over the past decade was aimed at antagonising IL-5 function. It appears from recent studies that, although this can easily be achieved in vitro, blocking IL-5 function in vivo is much more difficult than originally anticipated. Here, we review the current status of IL-5 and IL-5 receptor research, with emphasis on strategies to interfere with IL-5 function.
After its discovery in 1994, it soon became clear that leptin acts as an adipocyte-derived hormon... more After its discovery in 1994, it soon became clear that leptin acts as an adipocyte-derived hormone with a central role in the control of body weight and energy homeostasis. However, a growing body of evidence has revealed that leptin is a pleiotropic cytokine with activities on many peripheral cell types. Inappropriate leptin signaling can promote autoimmunity, certain cardiovascular diseases, elevated blood pressure and cancer, which makes leptin and the leptin receptor interesting targets for antagonism. Profound insights in the leptin receptor (LR) activation mechanisms are a prerequisite for the rational design of these antagonists. In this review, we focus on the molecular mechanisms underlying leptin receptor activation and signaling. We also discuss the current strategies to interfere with leptin signaling and their therapeutic potential.
Hemangioblastomas express erythropoietin and the patients often present with polycythemia. Serum ... more Hemangioblastomas express erythropoietin and the patients often present with polycythemia. Serum erythropoietin was measured using a commercial immunoassay, a functional erythropoietin assay and iso-electric focusing. Despite the polycythemia, serum erythropoietin remained low, while a functional erythropoietin-assay showed a 4-5 higher activity in serum compared to the immunoassay. Iso-electric focusing of serum erythropoietin indicated overrepresentation of highly sialylated erythropoietin isoforms produced by the tumor. As a result, altered affinity of the monoclonal antibody used in the immunoassay for the hypersialylated isoforms was suggested. Analysis of erythropoietin isoforms may be helpful in distinguishing the ectopic erythropoietin isoforms from normally glycosylated erythropoietin.
We have designed a sensitive and versatile bioassay for quantification of series of cytokines. Th... more We have designed a sensitive and versatile bioassay for quantification of series of cytokines. The assay makes use of chimeric receptors composed of the extracellular, ligand-binding part of the cognate cytokine receptor and the transmembrane and cytosolic part of the type I interferon receptor. Receptors can be homo- (e.g. erythropoietin), di- (e.g. interleukin-5), or even trimeric (e.g. interleukin-2). Stable expression of these chimeras in the 2fTGH cell line allows an interferon-type signaling, which makes a positive selection in conditioned medium possible or a negative selection using a toxic guanine analog. The cytokine of interest is quantified by the extent of cell survival or cell toxicity respectively, which can be measured by easy and cheap crystal violet staining. This bioassay is sensitive in the lower picogram per milliliter range and, in contrast to ELISA methods, only measures the concentration of biologically active cytokines. Using this approach, hypersensitive 2fTGH cell lines have been developed for type I and II interferons, erythropoietin, interleukin-2, and interleukin-5.
Leptin plays a central role in the control of body weight and energy homeostasis, but is a pleiot... more Leptin plays a central role in the control of body weight and energy homeostasis, but is a pleiotropic cytokine with activities on many peripheral cell types. In this review, we discuss the interaction of leptin with its receptor, and focus on the structural and mechanistic aspects of the extracellular aspects of leptin receptor (LR) activation. We provide an extensive overview of all structural information that has been obtained for leptin and its receptor via X-ray crystallography, electron microscopy, small-angle X-ray scattering, homology modeling, and mutagenesis studies. The available knowledge is integrated into putative models toward a recapitulation of the LR activation mechanism.
Leptin is a multifunctional hormone produced by the ob gene and is secreted by adipocytes that re... more Leptin is a multifunctional hormone produced by the ob gene and is secreted by adipocytes that regulate food intake and energy metabolism. Numerous studies demonstrated that leptin is a novel neuroprotective effector, however, the mechanisms are largely unknown. Herein, we demonstrate the protective activities of leptin after ischemic stroke and provide the first evidence for the involvement of the connexin 43 (Cx43) in leptin-mediated neuroprotection. We found that leptin treatment reduces the infarct volume, improves animal behavioral parameters, and inhibits the elevation of Cx43 expression in vivo. In vitro, leptin reverses ischemia-induced SY5Y and U87 cells Cx43 elevation, secreted glutamate levels in medium and SY5Y cell death, these roles could be abolished by leptin receptor blocker. Additionally, leptin administration upregulated the extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation. Moreover, ERK1/2 inhibitors pretreatment reversed the effects of leptin on...
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Papers by Lennart Zabeau