RESUMO
AIM: The purpose of this study was to contribute to content validity, by providing input into the linguistic and pragmatic validities, of a 53 item Psychological-Social-Spiritual Healing instrument. BACKGROUND: Discovery of cultural values and beliefs from African American elders' experiences of illness provides insight for development of more culturally sensitive instruments. METHODS: Through an exploratory descriptive design, this study used cognitive interviewing methods to examine linguistic and pragmatic validity of the Psychological-Social-Spiritual Healing instrument, from the perspectives of aging seriously ill AAs. Participants were recruited from urban Jackson, MS from community settings from October 2014 to January 2015. With a purposefully chosen sample of seriously ill African Americans elders (N=15), and using the method of cognitive interviewing, responses related to cultural relevance, clarity and meaning of the 53 items of the instrument were collected. This in-depth query of items was accomplished through the use of both verbal probing and think aloud methods of cognitive interviewing. RESULTS: Thirty-seven items were retained. Eight items were revised. Eight items were deleted. CONCLUSIONS: From the expert input of seriously ill African American elders, a systematic decision-making process of item retention, revision or deletion led to the development of a more culturally sensitive Psychological-Social-Spiritual Healing instrument.
Assuntos
Negro ou Afro-Americano/psicologia , Estado Terminal/psicologia , Idoso Fragilizado/psicologia , Cuidados Paliativos/psicologia , Qualidade de Vida/psicologia , Apoio Social , Terapias Espirituais/métodos , Idoso , Idoso de 80 Anos ou mais , Atitude Frente a Morte , Feminino , Humanos , Masculino , Mississippi , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
The foundation of culturally sensitive patient-centered palliative care is formed from one's social, spiritual, psychological, and physical experiences of serious illness. The purpose of this study was to describe categories and patterns of psychological, social, and spiritual healing from the perspectives of aging seriously ill African American (AA) elders. Using narrative analysis methodology, 13 open-ended interviews were collected. Three main patterns were "prior experiences," "I changed," and "across past, present experiences and future expectations." Themes were categorized within each pattern: been through it . . . made me strong, I thought about . . . others, went down little hills . . . got me down, I grew stronger, changed priorities, do things I never would have done, quit doing, God did and will take care of me, close-knit relationships, and life is better. "Faith" in God helped the aging seriously ill AA elders "overcome things," whether their current illness or other life difficulties.
Assuntos
Envelhecimento/psicologia , Atitude Frente a Morte , Negro ou Afro-Americano/psicologia , Estado Terminal/psicologia , Cuidados Paliativos/psicologia , Assistência Centrada no Paciente , Espiritualidade , Adaptação Psicológica , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
Some cancer survivors report positive subjective changes they describe as "life transforming." We used a grounded theory approach to identify the content, underlying process, and identifying characteristics of self-defined "life-transforming" changes (LTCs) reported by 9 cancer survivors. To actualize their hopes for improvement, participants used a self-guided process centered on pragmatic action: researching options, gaining experience, and frankly evaluating results. Many participants discovered unanticipated personal abilities and resources, and those became highly useful in coping with other challenges apart from cancer. This made the increased personal abilities and resources "life transforming" rather than being substantially limited to reducing cancer-related problems. The action-oriented features and processes of LTCs seemed to be more fully described by experiential learning theory than by posttraumatic growth and coping. Supportive intervention to facilitate positive change processes could decrease suffering and enhance positive psychosocial and spiritual outcomes for cancer survivors.
Assuntos
Adaptação Psicológica , Acontecimentos que Mudam a Vida , Neoplasias/psicologia , Resiliência Psicológica , Sobreviventes/psicologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/psicologia , Recidiva Local de Neoplasia/terapia , Neoplasias/terapia , Cuidados Paliativos/psicologia , Pesquisa Qualitativa , Autoeficácia , Papel do Doente , EspiritualidadeRESUMO
Unlike professional caregivers such as physicians and nurses, informal caregivers, typically family members or friends, provide care to individuals with a variety of conditions including advanced age, dementia, and cancer. This experience is commonly perceived as a chronic stressor, and caregivers often experience negative psychological, behavioral, and physiological effects on their daily lives and health. In this report, we describe the experience of a 53-year-old woman who is the sole caregiver for her husband, who has acute myelogenous leukemia and was undergoing allogeneic hematopoietic stem cell transplantation. During his intense and unpredictable course, the caregiver's burden is complex and complicated by multiple competing priorities. Because caregivers are often faced with multiple concurrent stressful events and extended, unrelenting stress, they may experience negative health effects, mediated in part by immune and autonomic dysregulation. Physicians and their interdisciplinary teams are presented daily with individuals providing such care and have opportunity to intervene. This report describes a case that exemplifies caregiving burden and discusses the importance of identifying caregivers at risk of negative health outcomes and intervening to attenuate the stress associated with the caregiving experience.
Assuntos
Cuidadores/psicologia , Efeitos Psicossociais da Doença , Nível de Saúde , Neoplasias/enfermagem , Estresse Psicológico , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enfermagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the body's stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF). This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF. In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF. Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed. Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress-related disorders.
Assuntos
Fadiga/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Doença Crônica , Suscetibilidade a Doenças , Fadiga/imunologia , Síndrome de Fadiga Crônica/fisiopatologia , Frequência Cardíaca/fisiologia , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiopatologia , Inflamação/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Saliva/metabolismo , alfa-Amilases/metabolismoRESUMO
The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy.
Assuntos
Receptores de Glucocorticoides/metabolismo , Toxinas Biológicas/toxicidade , Animais , Poluentes Ambientais/toxicidade , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Metais Pesados/toxicidade , Sistema Hipófise-Suprarrenal/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversosRESUMO
Clinicians have long known that a substantial proportion of patients treated with high-dose glucocorticoids experience a variety of serious side effects, including metabolic syndrome, bone loss, and mood shifts, such as depressive symptomatology, manic or hypomanic symptoms, and even suicide. The reason for individual variability in expression or severity of these side effects is not clear. However, recent emerging literature is beginning to shed light on possible mechanisms of these effects. As an introduction to this volume, this chapter will review the basic biology of glucocorticoid release and molecular mechanisms of glucocorticoid receptor function, and will discuss how dysregulation of glucocorticoid action at all levels could contribute to such side effects. At the molecular level, glucocorticoid receptor polymorphisms may be associated either with receptor hypofunction or hyperfunction and could thus contribute to differential individual sensitivity to the effects of glucocorticoid treatment. Numerous factors regulate hypothalamic-pituitary-adrenal (HPA) axis responsiveness, which could also contribute to individual differences in glucocorticoid side effects. One of these is sex hormone status and the influence of estrogen and progesterone on HPA axis function and mood. Another is immune system activity, in which immune molecules, such as interleukins and cytokines, activate the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines in inducing sickness behaviors, which overlap with depressive symptomatology, could also contribute to individual differences in such symptomatology. Taken together, this knowledge will have important relevance for identifying at-risk patients to avoid or minimize such side effects when they are treated with glucocorticoids. A framework for assessment of patients is proposed that incorporates functional, physiological, and molecular biomarkers to identify subgroups of patients at risk for depressive symptomatology associated with glucocorticoid treatment, and for prevention of side effects, which in many cases can be life-threatening.
Assuntos
Glucocorticoides/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/fisiopatologia , Transtorno Depressivo/induzido quimicamente , Transtorno Depressivo/patologia , Transtorno Depressivo/fisiopatologia , Previsões , Hormônios Esteroides Gonadais/farmacologia , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inibidoresRESUMO
We have recently shown that the anthrax lethal toxin (LeTx) selectively represses nuclear hormone receptors. In this study, we found that LeTx repressed the activation of the mouse mammary tumor virus promoter related to overexpression of the transcription factors hepatocyte nuclear factor 3, octamer-binding protein 1, and c-Jun. LeTx transcriptional repression was associated with a decrease in the protein levels of these transcription factors in a lethal factor protease activity-dependent manner. Early administration of LeTx antagonists partially or completely abolished the repressive effects of LeTx. In contrast to the rapid cleavage of mitogen-activated protein kinase kinases by LeTx, the degradation of these transcription factors occurred at a relatively late stage after LeTx treatment. In addition, LeTx repressed phorbol-12-myristate-13-acetate-induced mouse mammary tumor virus promoter activity and phorbol 12-myristate 13-acetate induction of endogenous c-Jun protein. Collectively, these findings suggest that transcription factors are intracellular targets of LeTx and expand our understanding of the molecular action of LeTx at a later stage of low-dose exposure.
Assuntos
Antígenos de Bactérias/metabolismo , Bacillus anthracis/metabolismo , Toxinas Bacterianas/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição/antagonistas & inibidores , Animais , Células COS , Chlorocebus aethiops , Genes Reporter , Vírus do Tumor Mamário do Camundongo/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
Measurement of protein expression in live, intact cells using flow cytometry (FC) has been employed for several decades in the areas of immunology, cell biology, and molecular biology. More recently, this technique has found appreciation in applied scientific fields, including cancer biology and endocrinology, to serve as a tool for identifying cells more likely to respond to specific treatments. FC, also referred to as fluorescence-activated cell sorting (FACS), is an antibody-based method that provides the user with an ability to identify proteins expressed on surfaces of cells as well as in the cytoplasm, including steroid hormone receptors. This technique is most useful for examining specific cell types in a heterogeneous population and therefore can be used to identify cells more likely to respond to treatments based on expression of the appropriate receptor. Isolation of purified subpopulations for further manipulation and investigation of functional capacity is also possible using a cell sorter, which uses similar technology to isolate cells for use by the researcher. This is especially important for studying responses of less abundant cell populations in tissues that express high levels of a target protein or receptor of interest. Furthermore, FACS analysis is clinically useful to identify and isolate responsive cell populations, which may be less appreciable in whole tissues because of the diluting effects of surrounding, nonresponding cell types. Immune cells are commonly utilized as a source of cell populations in the FC technique and have previously been shown to express steroid hormone receptors and respond to steroid hormone treatment. Here, we demonstrate that FC is a useful tool for identifying immune cells expressing steroid hormone receptor protein. This method can also be easily expanded to include other, nonimmune cell populations to address specific research questions related to steroid hormone receptor biology.
Assuntos
Citometria de Fluxo/métodos , Leucócitos/metabolismo , Receptores de Esteroides/metabolismo , Animais , Citometria de Fluxo/instrumentação , Leucócitos/citologia , Camundongos , Ratos , Receptores de Esteroides/genética , SoftwareRESUMO
BACKGROUND: Steroid hormones, such as progesterone, are known to have immunomodulatory effects. Our research group previously reported direct effects of progesterone on dendritic cells (DCs) from female rodents. Primarily affecting mature DC function, progesterone effects included inhibition of proinflammatory cytokine secretion, downregulation of cell surface marker (major histocompatibility complex class II, CD80) expression, and decreased T-cell proliferative capacity, and were likely mediated through progesterone receptor (PR) because the PR antagonist RU486 reversed these effects. OBJECTIVE: The goal of this study was to assess differences in response to progesterone by DCs from female and male rodents. METHODS: Using real-time reverse-transcriptase polymerase chain reaction, transcriptional expression of steroid hormone receptors was measured in immature bone marrow-derived DCs (BMDCs) from male and female rats. Expression of steroid hormone receptor protein was also assessed in these cells using flow cytometry and fluorescence microscopy. To evaluate functional differences between BMDCs from female and male rats in response to the steroid hormone progesterone, levels of secreted cytokines were measured using enzyme-linked immunosorbent assay. RESULTS: Higher numbers of immature BMDCs from males expressed glucocorticoid receptor (GR) and androgen receptor (AR) proteins compared with females (males vs females, mean [SD]: GR = 68.75 [7.27] vs 43.61 [13.97], P = NS; AR = 75.99 [15.38] vs 8.25 [1.88], P = 0.002), whereas higher numbers of immature BMDCs from females expressed PR protein compared with males (females vs males: PR = 74.19 [12.11] vs 14.14 [4.55], P = 0.043). These differences were not found at the level of transcription (females vs males: GR = 0.088 vs 0.073, P = NS; AR = 0.076 vs 0.069, P = NS; PR = 0.075 vs 0.065, P = NS). Compared with those from females, mature BMDCs from males produced higher quantities of cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, IL-10) (females vs males: TNF-alpha = 920.0 [79.25] vs 1100.61 [107.97], P = NS; IL-1beta = 146.60 [38.04] vs 191.10 [10.47], P = NS; IL-10 = 167.25 [4.50] vs 206.15 [23.48], P = NS). Conversely, BMDCs from females were more sensitive to progesterone, as indicated by a more dramatic reduction in proinflammatory cytokine secretion (females vs males, highest concentration of progesterone: TNF-alpha = 268.94 [28.59] vs 589.91 [100.98], P = 0.04; IL-1beta = 119.50 [10.32] vs 154.35 [6.22], P = NS). CONCLUSIONS: These findings suggest that progesterone effects on DCs in rodents may be more pronounced in females than in males, and this is likely due to differences in PR protein expression. Our observations may help elucidate disparities in the incidence and severity of autoimmune disorders between females and males, and the role specific steroid hormones play in regulating immune responses.
Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Progesterona/farmacologia , Progestinas/farmacologia , Caracteres Sexuais , Animais , Antígenos/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Separação Celular , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores de Progesterona/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A bidirectional communication exists between the CNS and the immune system. The autonomic nervous system, through neurotransmitters and neuropeptides, works in parallel with the hypothalamic-pituitary-adrenal axis through the actions of glucocorticoids to modulate inflammatory events. The immune system, through the action of cytokines and other factors, in turn, activates the CNS to orchestrate negative-feedback mechanisms that keep the immune response in check. Disruption of these interactions has been associated with a number of syndromes including inflammatory, autoimmune, and cardiovascular diseases, metabolic and psychiatric disorders, and the development of shock. The hypothalamic-pituitary-gonadal axis also plays an important part in regulating immunity through the secretion of sex hormones. Although numerous studies have established a role for immunomodulation by estrogen and testosterone, the role of progesterone is less well understood. Progesterone is crucial for reproductive organ development and maintenance of pregnancy, and more recent studies have clearly shown its role as an important immune regulator. The main focus of this review will be about the role of steroid hormones, specifically glucocorticoids and progesterone, in inflammatory responses and infectious diseases and how dysregulation of their actions may contribute to development of autoimmune and inflammatory disease.
Assuntos
Doenças Autoimunes/fisiopatologia , Glucocorticoides/fisiologia , Infecções/fisiopatologia , Inflamação/fisiopatologia , Progestinas/fisiologia , Progressão da Doença , Suscetibilidade a Doenças , Glucocorticoides/imunologia , Humanos , Infecções/imunologia , Inflamação/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Polimorfismo Genético , Progestinas/imunologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/imunologia , Receptores de Glucocorticoides/fisiologiaRESUMO
BACKGROUND: An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder (MDD), mostly women. METHODS: Study recruitment was conducted from July 1, 2001, to February 29, 2003. We report baseline BMD measurements in 89 premenopausal women with MDD and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual-energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women. We defined MDD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). RESULTS: The prevalence of low BMD, defined as a T score of less than -1, was greater in women with MDD vs controls at the femoral neck (17% vs 2%; P = .02) and total hip (15% vs 2%; P = .03) and tended to be greater at the lumbar spine (20% vs 9%; P = .14). The mean +/- SD BMD, expressed as grams per square centimeters, was lower in women with MDD at the femoral neck (0.849 +/- 0.121 vs 0.866 +/- 0.094; P = .05) and at the lumbar spine (1.024 +/- 0.117 vs 1.043 +/- 0.092; P = .05) and tended to be lower at the radius (0.696 +/- 0.049 vs 0.710 +/- 0.055; P = .07). Women with MDD had increased mean levels of 24-hour proinflammatory cytokines and decreased levels of anti-inflammatory cytokines. CONCLUSIONS: Low BMD is more prevalent in premenopausal women with MDD. The BMD deficits are of clinical significance and comparable in magnitude to those resulting from established risk factors for osteoporosis, such as smoking and reduced calcium intake. The possible contribution of immune or inflammatory imbalance to low BMD in premenopausal women with MDD remains to be clarified.
Assuntos
Densidade Óssea , Transtorno Depressivo/fisiopatologia , Pré-Menopausa/fisiologia , Absorciometria de Fóton , Adulto , Doenças Ósseas/etiologia , Doenças Ósseas/fisiopatologia , Catecolaminas/urina , Transtorno Depressivo/complicações , Transtorno Depressivo/diagnóstico , Feminino , Humanos , Hidrocortisona/urina , Interleucina-10/sangue , Interleucina-13/sangue , Interleucina-1beta/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Pré-Menopausa/sangue , Pré-Menopausa/urina , Estudos Prospectivos , Fator de Necrose Tumoral alfa/sangueAssuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Artrite Reumatoide/imunologia , Biomarcadores/metabolismo , Desidroepiandrosterona/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores do Fator de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
We have previously shown that Bacillus anthracis lethal toxin represses glucocorticoid receptor (GR) transactivation. We now report that repression of GR activity also occurs with the large clostridial toxins produced by Clostridium sordellii and C. difficile. This was demonstrated using a transient transfection assay system for GR transactivation. We also report that C. sordellii lethal toxin inhibited GR function in an ex vivo assay, where toxin reduced the dexamethasone suppression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Furthermore, the glucocorticoid antagonist RU-486 in combination with C. sordellii lethal toxin additively prevented glucocorticoid suppression of TNF-alpha. These findings corroborate the fact that GR is a target for the toxin and suggest a physiological role for toxin-associated GR repression in inflammation. Finally, we show that this repression is associated with toxins that inactivate p38 mitogen-activated protein kinase (MAPK).
Assuntos
Proteínas de Bactérias/farmacologia , Toxinas Bacterianas/farmacologia , Clostridioides difficile/fisiologia , Clostridium sordellii/fisiologia , Enterotoxinas/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Fusão Gênica Artificial , Células COS , Chlorocebus aethiops , Dexametasona/antagonistas & inibidores , Dexametasona/farmacologia , Genes Reporter , Glucocorticoides/antagonistas & inibidores , Glucocorticoides/farmacologia , Luciferases/análise , Luciferases/genética , Fosforilação , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
OBJETIVO: Nesta revisão será focado o papel das citocinas no sistema nervoso central e suas implicações para o quadro depressivo. Posteriormente, serão discutidos os principais achados sobre medidas de citocinas em pacientes com depressão maior. MÉTODO: Foi realizada uma pesquisa no Pubmed selecionando estudos entre 1999-2007, utilizando as seguintes palavras-chave: "depression, cytokine"; "depressive disorder, cytokine". Focou-se nos estudos de medidas de citocinas pró-inflamatórias em pacientes com síndrome depressiva que utilizaram critérios DSM. RESULTADOS: Várias linhas de evidência sugerem que as citocinas possam exercer um papel na depressão. Entre elas, destacam-se: citocinas induzindo a "comportamento doentio"; doenças clínicas relacionadas com citocinas também apresentam associação com quadros depressivos; uso de imunoterapia levando ao desenvolvimento de depressão. Além disso, níveis elevados de citocinas pró-inflamatórias em pacientes com depressão foram relatados, apesar de resultados contraditórios. CONCLUSÃO: O papel das citocinas na fisiopatologia em alguns casos de depressão é descrito; porém, uma relação causal não foi ainda estabelecida. Novos estudos são necessários para determinar padrões específicos de citocinas em pacientes com depressão, levando em consideração outros fatores associados à ativação imunológica. Além disso, medidas simultâneas de múltiplos marcadores biológicos podem gerar informações importantes para a compreensão dos mecanismos fisiopatológico da depressão e em doenças relacionadas à produção de citocinas.
OBJECTIVE: This review will focus on the role of cytokines in the central nervous system and its implications to depressive disorder. We will then discuss the main findings of cytokine measurements in patients with major depressive disorder. METHOD: We searched Pubmed for studies published from 1999-2007, using the keywords depression and cytokine; and depressive disorder and cytokine. We have focused on pro-inflammatory cytokine measurements in patients with depression syndrome using DSM-criteria. RESULTS: Several lines of evidence suggest that cytokines have effects on depression, such as the induction of sickness behavior; clinical conditions related to cytokines that also overlap depressive symptoms; and immunotherapy that can lead to depressive symptoms attenuated by antidepressant treatment. Finally, patients with depression exhibit increased levels of pro-inflammatory cytokines, although conflicting results have been described. CONCLUSION: Cytokines may play a role in the pathophysiology of some cases of depression, although a causal link has not been established yet. Further longitudinal studies are needed to determine patterns of cytokine in patients with major depressive disorder, taking into account confounding factors closely associated with the activation of pro-inflammatory cytokines. In addition, simultaneous measurements of multiple biomarkers could provide critical insights into mechanisms underlying major depressive disorder and a variety of common cytokine-related diseases.
Assuntos
Humanos , Encéfalo/imunologia , Citocinas/fisiologia , Depressão/fisiopatologia , Transtorno Depressivo/fisiopatologia , Sistema Imunitário , Neuroimunomodulação/fisiologia , Antidepressivos/uso terapêutico , Biomarcadores/metabolismo , Citocinas/metabolismo , Depressão/imunologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Estresse Psicológico/fisiopatologiaRESUMO
A variety of extraimmune system factors, including hormones, play a critical role in regulating immunity. Progesterone has been shown to affect immunity in rodents and humans, mainly at concentrations commensurate with pregnancy. These effects are primarily mediated via the progesterone receptor (PR), which acts as a transcription factor, although non-genomic effects of PR activation have been reported. In this study, we evaluated the effects of progesterone on rat dendritic cells (DCs) at ranges encompassing physiologic and pharmacologic concentrations to determine whether progesterone plays a role in modulating DC-mediated immune responses. DCs were derived by culturing rat bone marrow cells in granulocyte macrophage colony-stimulating factor and IL-4. Cells were analyzed for expression of PR using FACS analysis, real-time reverse transcriptase-PCR and fluorescent microscopy. Progesterone treatment of LPS-activated, mature bone marrow-derived dendritic cells (BMDCs) suppressed production of the pro-inflammatory response-promoting cytokines tumor necrosis factor-alpha and IL-1beta in a dose-dependent manner but did not affect production of the pro-inflammatory response-inhibiting cytokine IL-10. Treatment of cells with progesterone also resulted in down-regulation of co-stimulatory molecule CD80 and MHC class II molecule RT1B expression. In addition, progesterone inhibited DC-stimulated proliferation of T cells. Suppression of pro-inflammatory response-promoting cytokine production by progesterone was prevented using the PR antagonist RU486. There was no dose-dependent effect of progesterone treatment on immature DC capacity to take up antigenic peptide. These data indicate that progesterone directly inhibits mature rat BMDC capacity to drive pro-inflammatory responses. This mechanism could contribute to or account for some of the differential expression of autoimmune/inflammatory disease in females.
Assuntos
Células da Medula Óssea/metabolismo , Células Dendríticas/metabolismo , Progesterona/metabolismo , Progestinas/metabolismo , Receptores de Progesterona/metabolismo , Animais , Antígenos/metabolismo , Antígeno B7-1/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Separação Celular , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Antígenos de Histocompatibilidade/metabolismo , Antagonistas de Hormônios/farmacologia , Interleucina-1beta/metabolismo , Ativação Linfocitária , Microscopia de Fluorescência , Mifepristona/farmacologia , Progesterona/genética , Progesterona/farmacologia , Progestinas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores de Progesterona/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Bacillus anthracis lethal toxin (LT) causes vascular collapse and high lethality in BALB/cJ mice, intermediate lethality in C57BL/6J mice, and no lethality in DBA/2J mice. We found that adrenalectomized (ADX) mice of all three strains had increased susceptibility to LT. The increased susceptibility of ADX-DBA/2J mice was not accompanied by changes in their macrophage sensitivity or cytokine response to LT. DBA/2J mice showed no change in serum corticosteroid levels in response to LT injection, while BALB/cJ mice showed a fivefold increase in serum corticosterone. However, LT inhibited dexamethasone (DEX)-induced glucocorticoid receptor gene activation to similar extents in all three strains. DEX treatment did not rescue ADX mice from LT-mediated mortality. Surprisingly, oral DEX treatment also sensitized adrenally intact DBA/2J mice to LT lethality at all doses tested and also exacerbated LT-mediated pathogenesis and mortality in BALB/cJ mice. Aldosterone did not protect ADX mice from toxin challenge. These results indicate that susceptibility to anthrax LT in mice depends on a fine but easily perturbed balance of endocrine functions. Thus, the potentially detrimental consequences of steroid therapy for anthrax must be considered in treatment protocols for this disease.
Assuntos
Antígenos de Bactérias/toxicidade , Toxinas Bacterianas/toxicidade , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Adrenalectomia , Aldosterona/uso terapêutico , Animais , Corticosterona/sangue , Citocinas/biossíntese , Dexametasona/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Receptores de Glucocorticoides/fisiologiaRESUMO
The function of pro-inflammatory cytokines and chemokines in brain injury and autoimmune diseases has been long recognized. There is however, a significant lack of information regarding the role of constitutively expressed immune genes in the normal brain. The current evidence points to the involvement of certain cytokines and major histocompatibility complex (MHC) molecules in synaptic function and plasticity. Furthermore, constitutively expressed chemokines in neurons provide an additional indication of a role for these molecules in neural function. In addition, clinical data suggests a dysregulation of immune genes in the cerebrospinal fluid of psychiatric patients who have neither brain injury nor autoimmune diseases. This review will discuss recent data indicating a role for immune genes in synaptic stability and will also discuss the implications for specific brain functions involving mood and cognition.
Assuntos
Regulação da Expressão Gênica , Neurônios/metabolismo , Transmissão Sináptica , Animais , Encéfalo/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Glutamina/metabolismo , Humanos , Sistema Imunitário , Inflamação , Complexo Principal de Histocompatibilidade , Transtornos Mentais/líquido cefalorraquidiano , Sinapses/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Death from anthrax has been reported to occur from systemic shock. The lethal toxin (LeTx) is the major effector of anthrax mortality. Although the mechanism of entry of this toxin into cells is well understood, its actions once inside the cell are not as well understood. LeTx is known to cleave and inactivate MAPKKs. We have recently shown that LeTx represses the glucocorticoid receptor (GR) both in vitro and in vivo. This repression is partial and specific, repressing the glucocorticoid, progesterone, and estrogen receptor alpha, but not the mineralocorticoid or estrogen receptor beta. This toxin does not affect GR ligand or DNA binding, and we have suggested that it may function by removing/inactivating one or more of the many cofactors involved in nuclear hormone receptor signaling. Although the precise involvement of this nuclear hormone receptor repression in LeTx toxicity is unknown, examples of blunted HPA axis and glucocorticoid signaling in numerous autoimmune/inflammatory diseases suggest that such repression of critically important receptors could have deleterious effects on health.