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Preliminary evidence that bereavement is associated with reduced neutrophil function
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Abstracts / Brain, Behavior, and Immunity 24 (2010) S1–S71
The kynurenine pathway (KP) of tryptophan metabolism is one of the major regulatory mechanisms of the immune response. Activation of the KP is implicated in the pathogenesis of a wide range of neuroinflammatory diseases. Several pro-inflammatory mediators can activate indoleamine 2,3 dioxygenase (IDO-1) the first and regulatory enzyme of the KP. A prolonged activation of the KP leads to production and accumulation of several neurotoxins including the potent excitotoxin quinolinic acid (QUIN). Every single brain cell types appear to express differently the KP enzymes and producing different KP metabolites. Neurons, astrocytes, oligodendrocytes and brain microvascular endothelial cells produce neuroprotective compounds whereas activated microglia, pericytes, infiltrating macrophages synthesize and release neurotoxic KP metabolites. This dynamic and complex interplay between KP metabolites from different brain and immune cells is directly involved in the global and progressive inflammatory response involved in the neuropathogenesis of several major neurodegenerative diseases including Alzheimer’s disease, motor neuron diseases, Parkinson’s disease, multiple sclerosis. doi:10.1016/j.bbi.2010.07.225
Abstract # 505 Preliminary evidence that bereavement is associated with reduced neutrophil function R. Suliman Khanfer a, A.C. Phillips a, D. Carroll a, J. Lord a,b a
University of Birmingham, School of Sport and Exercise Sciences, Edgbaston, Birmingham B15 2TT, UK b School of Immunity and Infection, UK
The underlying mechanisms for the effects of stress and other biobehavioral factors on cancer growth and progression are poorly understood. We have performed a series of in vitro and in vivo experiments to identify specific neuroendocrine signaling pathways that mediate direct effects of chronic stress on tumor cell biology. Findings indicate that chronic stress affects multiple steps during metastasis, resulting in greater tumor burden and more invasive growth. Moreover, catecholamines modulate the expression of genes encoding angiogenic factors (e.g., VEGF) via b-adrenergic receptors expressed on the human tumor cell surface. These effects are mediated primarily through activation of the tumor cell cAMP-PKA signaling pathway. Recent data also demonstrate that human cancer cells exposed to norepinephrine or epinephrine exhibit lower levels of anoikis, the process by which cells enter apoptosis when separated from extracellular matrix and neighboring cells. In orthotopic mouse models of human ovarian cancer, restraint stress and the associated increases in norepinephrine and epinephrine protected the tumor cells from anoikis and promoted their growth by activating focal adhesion kinase (FAK). Importantly, in human ovarian cancer patients, behavioral states related to greater adrenergic activity were associated with higher levels of pFAKY397, which was in turn linked to substantially accelerated mortality. Characterizing these pathways by which chronic stress provides support for angiogenesis and other steps in metastasis could have therapeutic implications for cancer management. doi:10.1016/j.bbi.2010.07.227
Abstract # 507 Bereavement is considered one of the most stressful life events; previous studies have shown that bereavement is associated with increased morbidity and mortality. A few studies have explored the impact of bereavement on immunity but not in neutrophils. Neutrophils are white blood cells forming the main component of our innate immunity. Disturbances in neutrophil number or function are associated with serious recurrent infection. The aim of this study is to examine the effect of recent bereavement (<2 months) on neutrophil function, specifically phagocytosis of Escherichia coli and stimulated superoxide production among older adults >65. Participants were 36 (22 female) aged 65 years or older (20 bereaved and 16 age- and sex-matched controls). Blood samples to determine neutrophil function by flow cytometry were taken within 2 months of bereavement. There was a reduction of neutrophil superoxide production associated with the bereavement, when neutrophils were challenged with either E. coli or PMA. There was no difference in the phagocytosis between the two groups. Further, preliminary analysis shows that the bereaved had a higher cortisol:DHEAS ratio compared to controls. Given the co-existence of immunosenescence, this could help to explain previous associations between bereavement and higher morbidity and mortality in older adults. doi:10.1016/j.bbi.2010.07.226
Abstract # 506 Molecular and biological effects of stress on cancer metastasis A. Sood UT M.D. Anderson Cancer Center, Gynecologic Oncology, P.O. Box 301439, Unit 1362, Houston, TX 77230, United States
Stress, anxiety, & susceptibility to skin cancer F.S. Dhabhar Department of Psychiatry & Behavioral Sciences, Institute for Immunity Transplantation & Infection, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, United States While chronic stress suppresses/dysregulates immune function, under certain conditions an acute/short-term stress response experienced during immune activation can enhance primary/innate and secondary/adaptive immunity. Recent studies have examined these effects of stress using a naturalistic model of skin cancer (squamous cell carcinoma (SCC)) that provides a non-invasive system for studying tumor emergence and progression. Mice were exposed to chronic or acute stress during weeks 4–6 of a 10-week UV-exposure protocol (minimum-erythemal-dose, 3-times/week). Chronic stress suppressed CTACK, IL-12 and IFN-gamma gene expression, decreased CD4+ and CD8+ T cell infiltration, and significantly increased tumor burden. Interestingly, chronic stress also increased numbers of tumor-infiltrating and circulating regulatory T cells, which represents a novel immuno-suppressive mechanism mobilized by chronic stress (Saul et al., JNCI, 2005). In contrast, acute stress enhanced CTACK, IL-12, and IFN-gamma gene expression, increased CD4+ and CD8+ T cell infiltration, and decreased tumor burden during the early phase of tumor development (Dhabhar et al., BBI, 2010). We also examined the effects of anxiety-like behavioral phenotypes on susceptibility to SCC. Mice showing a high-anxiety phenotype at baseline showed lower protective immunity, and increased susceptibility to SCC compared to lowanxiety mice. These studies add to a growing understanding of how factors like stress and anxiety may affect tumor development and anti-tumor immunity, which is important for tumors that are
Abstracts / Brain, Behavior, and Immunity 24 (2010) S1–S71
The kynurenine pathway (KP) of tryptophan metabolism is one of the major regulatory mechanisms of the immune response. Activation of the KP is implicated in the pathogenesis of a wide range of neuroinflammatory diseases. Several pro-inflammatory mediators can activate indoleamine 2,3 dioxygenase (IDO-1) the first and regulatory enzyme of the KP. A prolonged activation of the KP leads to production and accumulation of several neurotoxins including the potent excitotoxin quinolinic acid (QUIN). Every single brain cell types appear to express differently the KP enzymes and producing different KP metabolites. Neurons, astrocytes, oligodendrocytes and brain microvascular endothelial cells produce neuroprotective compounds whereas activated microglia, pericytes, infiltrating macrophages synthesize and release neurotoxic KP metabolites. This dynamic and complex interplay between KP metabolites from different brain and immune cells is directly involved in the global and progressive inflammatory response involved in the neuropathogenesis of several major neurodegenerative diseases including Alzheimer’s disease, motor neuron diseases, Parkinson’s disease, multiple sclerosis. doi:10.1016/j.bbi.2010.07.225
Abstract # 505 Preliminary evidence that bereavement is associated with reduced neutrophil function R. Suliman Khanfer a, A.C. Phillips a, D. Carroll a, J. Lord a,b a
University of Birmingham, School of Sport and Exercise Sciences, Edgbaston, Birmingham B15 2TT, UK b School of Immunity and Infection, UK
The underlying mechanisms for the effects of stress and other biobehavioral factors on cancer growth and progression are poorly understood. We have performed a series of in vitro and in vivo experiments to identify specific neuroendocrine signaling pathways that mediate direct effects of chronic stress on tumor cell biology. Findings indicate that chronic stress affects multiple steps during metastasis, resulting in greater tumor burden and more invasive growth. Moreover, catecholamines modulate the expression of genes encoding angiogenic factors (e.g., VEGF) via b-adrenergic receptors expressed on the human tumor cell surface. These effects are mediated primarily through activation of the tumor cell cAMP-PKA signaling pathway. Recent data also demonstrate that human cancer cells exposed to norepinephrine or epinephrine exhibit lower levels of anoikis, the process by which cells enter apoptosis when separated from extracellular matrix and neighboring cells. In orthotopic mouse models of human ovarian cancer, restraint stress and the associated increases in norepinephrine and epinephrine protected the tumor cells from anoikis and promoted their growth by activating focal adhesion kinase (FAK). Importantly, in human ovarian cancer patients, behavioral states related to greater adrenergic activity were associated with higher levels of pFAKY397, which was in turn linked to substantially accelerated mortality. Characterizing these pathways by which chronic stress provides support for angiogenesis and other steps in metastasis could have therapeutic implications for cancer management. doi:10.1016/j.bbi.2010.07.227
Abstract # 507 Bereavement is considered one of the most stressful life events; previous studies have shown that bereavement is associated with increased morbidity and mortality. A few studies have explored the impact of bereavement on immunity but not in neutrophils. Neutrophils are white blood cells forming the main component of our innate immunity. Disturbances in neutrophil number or function are associated with serious recurrent infection. The aim of this study is to examine the effect of recent bereavement (<2 months) on neutrophil function, specifically phagocytosis of Escherichia coli and stimulated superoxide production among older adults >65. Participants were 36 (22 female) aged 65 years or older (20 bereaved and 16 age- and sex-matched controls). Blood samples to determine neutrophil function by flow cytometry were taken within 2 months of bereavement. There was a reduction of neutrophil superoxide production associated with the bereavement, when neutrophils were challenged with either E. coli or PMA. There was no difference in the phagocytosis between the two groups. Further, preliminary analysis shows that the bereaved had a higher cortisol:DHEAS ratio compared to controls. Given the co-existence of immunosenescence, this could help to explain previous associations between bereavement and higher morbidity and mortality in older adults. doi:10.1016/j.bbi.2010.07.226
Abstract # 506 Molecular and biological effects of stress on cancer metastasis A. Sood UT M.D. Anderson Cancer Center, Gynecologic Oncology, P.O. Box 301439, Unit 1362, Houston, TX 77230, United States
Stress, anxiety, & susceptibility to skin cancer F.S. Dhabhar Department of Psychiatry & Behavioral Sciences, Institute for Immunity Transplantation & Infection, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, United States While chronic stress suppresses/dysregulates immune function, under certain conditions an acute/short-term stress response experienced during immune activation can enhance primary/innate and secondary/adaptive immunity. Recent studies have examined these effects of stress using a naturalistic model of skin cancer (squamous cell carcinoma (SCC)) that provides a non-invasive system for studying tumor emergence and progression. Mice were exposed to chronic or acute stress during weeks 4–6 of a 10-week UV-exposure protocol (minimum-erythemal-dose, 3-times/week). Chronic stress suppressed CTACK, IL-12 and IFN-gamma gene expression, decreased CD4+ and CD8+ T cell infiltration, and significantly increased tumor burden. Interestingly, chronic stress also increased numbers of tumor-infiltrating and circulating regulatory T cells, which represents a novel immuno-suppressive mechanism mobilized by chronic stress (Saul et al., JNCI, 2005). In contrast, acute stress enhanced CTACK, IL-12, and IFN-gamma gene expression, increased CD4+ and CD8+ T cell infiltration, and decreased tumor burden during the early phase of tumor development (Dhabhar et al., BBI, 2010). We also examined the effects of anxiety-like behavioral phenotypes on susceptibility to SCC. Mice showing a high-anxiety phenotype at baseline showed lower protective immunity, and increased susceptibility to SCC compared to lowanxiety mice. These studies add to a growing understanding of how factors like stress and anxiety may affect tumor development and anti-tumor immunity, which is important for tumors that are