Search

Copyright of Revista de Gastroenterología del Perú is the property of Sociedad de Gastroenterologia del Peru and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The neuro-endocrine regulation of immune functions is based on a complex network of interactions. As part of this series of articles, we refer here to immune-sympathetic interactions that are triggered by different types of immune challenge. Summary: We mention the initial hypothesis that led to the proposal that the sympathetic nervous system (SNS) is involved in immunoregulation. We next refer mainly to our initial work performed at a time when most immunologists were concentrated in clarifying aspects of the immune system that are essential for its regulation from within. The first approach was to explore whether immune responses to innocuous antigens and superantigens can elicit changes in the activity of the SNS, and their potential relevance for the regulation of the activity of the immune system. The following step was to explore whether comparable immune-SNS interactions are detected in different models of diseases with immune components, such as parasitic and viral infections and autoimmune pathologies. Key Messages: We pose some general considerations that may at least partially explain seemly discrepant findings, and remark the importance of interpreting immunoregulatory effects of the SNS together with other neuro-endocrine inputs that simultaneously occur when the activity of the immune system changes. Finally, we provide some arguments to re-consider the use of the expression "reflex" in immunology. [ABSTRACT FROM AUTHOR]

Introduction: Targeting the α7 nicotinic acetylcholine receptor (α7nAChR) has recently been suggested as a potential new treatment for fibrotic skin diseases. Here, we performed a genetic and pharmacologic approach to clarify the role of this receptor in the bleomycin (BLM) mouse model of skin fibrosis using α7nAChR KO mice. Methods: We analyzed the expression of extracellular matrix (ECM) components in murine skin using quantitative RT-PCR, pepsin digestion/SDS-PAGE of proteins and performed hydroxyproline assays as well as histological/immunohistochemical staining of skin sections. To identity the target cells of the α7nAChR agonist PHA-543613, we used murine dermal fibroblasts (MDF). We tested their response to the profibrotic cytokine transforming growth factor-β1 (TGF-β1) and utilized gene silencing to elucidate the role of the α7nAChR. Results: We confirmed our previous findings on C3H/HeJ mice and detected a suppressive effect of PHA-543613 on BLM-induced skin fibrosis in the mouse strain C57BL/6J. This antifibrotic effect of PHA-543613 was abrogated in α7nAChR-KO mice. Interestingly, α7nAChR-KO animals exhibited a basal profibrotic signature by higher RNA expression of ECM genes and hydroxyproline content than WT mice. In WT MDF, PHA-543613 suppressed ECM gene expression induced by TGF-β1. Gene silencing of α7nAChR by small interfering RNA neutralized the effects of PHA-543613 on TGF-β1-mediated ECM gene expression. Conclusion: In summary, we have identified the α7nAChR as the essential mediator of the antifibrotic effect of PHA-543613. MDF are directly targeted by PHA-543613 to suppress collagen synthesis. Our findings emphasize therapeutic exploitation of α7nAChR receptor agonists in fibrotic skin diseases. [ABSTRACT FROM AUTHOR]

Evidence suggests that natural and adaptive immune responses can trigger neuroendocrine responses. Here, we discuss changes in the activity of the hypothalamus–pituitary–adrenal axis and in autonomic nerves, predominantly of the sympathetic nervous system, in a mouse model of acute infection with Trypanosoma cruzi. The endocrine response includes a marked increased release of glucocorticoid and a decrease of immune‐stimulatory hormones, such as dehydroepiandrosterone sulfate, prolactin, and growth hormone during infection. These endocrine changes result in reduced proinflammatory cytokine production, increased regulatory/effector T cell ratio, and thymus atrophy. The sympathetic activity in the spleen of infected mice is also markedly reduced. However, the residual sympathetic activity can modulate the immune response to the parasite, as shown by increased mortality and production of proinflammatory cytokines in sympathetically denervated, infected mice. The outcome of the neuroendocrine response is the moderation of the intensity of the immune response to the parasite, an effect that results in delayed mortality in susceptible mice, and favors the course toward chronicity in more resistant animals. Evidence suggests that natural and adaptive immune responses can trigger neuroendocrine responses. Here, we discuss changes in the activity of the hypothalamus–pituitary–adrenal axis and in autonomic nerves, predominantly of the sympathetic nervous system, in a mouse model of acute infection with Trypanosoma cruzi. [ABSTRACT FROM AUTHOR]

Ultrasonic vocalizations (USVs) serve important communicative functions in rodents. Different types of USVs can be triggered in the sender, for example, by maternal separation, social interactions, or exposure to predators, and they evoke affiliative or alarming behaviors in recipients. This review focusses on studies evaluating possible links between immunity and USVs. Most studies have been performed in a murine model of maternal immune activation and subsequent evaluation of effects in the offspring. This model has received large attention in recent years because it mimics behavioral abnormalities observed in certain human neuropsychiatric disorders, including autism spectrum disorder. Although there is still some controversy, the results indicate that stimulation of the immune system of mice and rats during pregnancy affects ultrasonic calling in pups. Few studies are available on immunization during adulthood and USVs. In most cases, immune stimulation led to disease, complicating conclusions about a possible direct link between vocalization and immunity. Although much work is still needed, this is certainly a rather new and promising aspect of interactions between the immune system and behavior. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to analyze the immune-endocrine profile in neurocysticercosis (NC) patients resistant to cysticidal treatment. Methods: The inflammatory and regulatory responses of 8 resistant NC patients with extraparenchymal parasites and 5 healthy controls were evaluated through flow cytometry. Serum interleukin levels were measured by ELISA and catecholamines levels by high performance liquid chromatography. Results: Higher percentages of Tr1, CD4+CD25+FOXP3+CD127– and CD4+CD45RO+FOXP3HI were found in NC patients compared with healthy controls, but no difference was found in catecholamine levels. Antigen-specific proliferative immune response was observed in NC patients. Neither anti-inflammatory nor pro-inflammatory cytokines showed differences between patients and controls, but IL-6 levels were lower in treatment-resistant NC patients. In addition, TGFβ showed a significant negative correlation with dopamine. Conclusions: Altogether, these results may point to a modulation of the neuroinflammation in these patients that could indirectly favor cysticercal survival in CNS microenvironment. [ABSTRACT FROM AUTHOR]

Depression has been associated with peripheral inflammatory processes and alterations in cellular immunity. Growing evidence suggests that immunological alterations may neither be necessary nor sufficient to induce depression in general, but seem to be associated with specific features. Using baseline data from the Outcome of Psychological Interventions in Depression trial, this exploratory study examines associations between depression subtypes and pathogenetic characteristics (i.e., melancholic vs non-melancholic depression, chronic vs non-chronic depression, age of onset, cognitive-affective and somatic symptom dimensions) with plasma levels of C-reactive protein (CRP), interleukin (IL)-6, IL-10, and numbers of leukocyte subpopulations in 98 patients with major depression (MD) and 30 age and sex-matched controls. Patients with MD exhibited higher CRP levels, higher neutrophil and monocyte counts, lower IL-10 levels, and an increased neutrophil to lymphocyte ratio (NLR) than controls. Patient with later age of onset had higher levels of two inflammatory markers (CRP, NLR) and lower cytotoxic T cell counts after adjusting for sociodemographics, lifestyle factors, and antidepressants. Furthermore, lower anti-inflammatory IL-10 levels were related to more severe somatic depressive symptoms. These results confirm and extend previous findings suggesting that increased levels of CRP are associated with a later onset of depression and demonstrate that also NLR as a subclinical inflammatory marker is related to a later onset of depression. Depression has been associated with peripheral inflammatory processes and alterations in cellular immunity. Growing evidence suggests that immunological alterations may neither be necessary nor sufficient to induce depression in general, but seem to be associated with specific features. Using baseline data from the Outcome of Psychological Interventions in Depression trial, this exploratory study examines associations between depression subtypes and pathogenetic characteristics (i.e., melancholic vs non-melancholic depression, chronic vs non-chronic depression, age of onset, cognitive-affective and somatic symptom dimensions) with plasma levels of C-reactive protein (CRP), interleukin (IL)-6, IL-10, and numbers of leukocyte subpopulations in 98 patients with major depression (MD) and 30 age and sex-matched controls. Patients with MD exhibited higher CRP levels, higher neutrophil and monocyte counts, lower IL-10 levels, and an increased neutrophil to lymphocyte ratio (NLR) than controls. Patient with later age of onset had higher levels of two inflammatory markers (CRP, NLR) and lower cytotoxic T cell counts after adjusting for sociodemographics, lifestyle factors, and antidepressants. Furthermore, lower anti-inflammatory IL-10 levels were related to more severe somatic depressive symptoms. These results confirm and extend previous findings suggesting that increased levels of CRP are associated with a later onset of depression and demonstrate that also NLR as a subclinical inflammatory marker is related to a later onset of depression. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a health problem worldwide. Patients with pulmonary TB show a neuro-immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro- and anti-inflammatory cytokines and markedly decreased dehydroepiandrosterone (DHEA) levels. Extending these findings, we now investigated the immune-endocrine profile of TB patients undergoing specific treatment. Patients (n = 24) were bled at diagnosis (T0), 2, 4, 6 months after treatment initiation and 3 months following its completion. At T0, TB patients showed increased plasma levels of interleukin-6 (IL-6), C reactive protein, interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-β). These mediators decreased during treatment, reaching levels similar to those from healthy controls (n = 26). Specific treatment led to an increased lymphoproliferative response along with clinical improvement. Newly diagnosed patients had low levels of DHEA, with increased cortisol amounts and cortisol/DHEA ratio, which normalized upon specific treatment. As regards glucocorticoid receptors (GR), TB patients at diagnosis presented a reduced mRNA GRα/GRβ ratio in their peripheral blood mononuclear cells. Furthermore, multivariate analysis showed that cortisol/DHEA ratio was positively associated with inflammatory mediators for which this ratio may constitute a disease biomarker. Anti-mycobacterial treatment results in a better immune-endocrine scenario for the control of physiopathological processes accompanying disease development and hence implied in clinical recovery. [ABSTRACT FROM AUTHOR]

Copyright of Revista de la ALAD is the property of Publicidad Permanyer SLU and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Specialized epithelial cells with a tuft of apical microvilli ('brush cells') sense luminal content and initiate protective reflexes in response to potentially harmful substances. They utilize the canonical taste transduction cascade to detect 'bitter' substances such as bacterial quorum-sensing molecules. In the respiratory tract, most of these cells are cholinergic and are approached by cholinoceptive sensory nerve fibers. Utilizing two different reporter mouse strains for the expression of choline acetyltransferase (ChAT), we observed intense labeling of a subset of thymic medullary cells. ChAT expression was confirmed by in situ hybridization. These cells showed expression of villin, a brush cell marker protein, and ultrastructurally exhibited lateral microvilli. They did not express neuroendocrine (chromogranin A, PGP9.5) or thymocyte (CD3) markers but rather thymic epithelial (CK8, CK18) markers and were immunoreactive for components of the taste transduction cascade such as Gα-gustducin, transient receptor potential melastatin-like subtype 5 channel (TRPM5), and phospholipase C. Reverse transcription and polymerase chain reaction confirmed the expression of Gα-gustducin, TRPM5, and phospholipase C. Thymic 'cholinergic chemosensory cells' were often in direct contact with medullary epithelial cells expressing the nicotinic acetylcholine receptor subunit α3. These cells have recently been identified as terminally differentiated epithelial cells (Hassall's corpuscle-like structures in mice). Contacts with nerve fibers (identified by PGP9.5 and CGRP antibodies), however, were not observed. Our data identify, in the thymus, a previously unrecognized presumptive chemosensitive cell that probably utilizes acetylcholine for paracrine signaling. This cell might participate in intrathymic infection-sensing mechanisms. [ABSTRACT FROM AUTHOR]

Objective There is increasing evidence that serotonin (5-hydroxytryptamine [5-HT]) and distinct 5-HT receptors are involved in the pathogenesis of systemic sclerosis. The aim of this study was to test the hypothesis that tropisetron, a routinely used antiemetic agent previously characterized as a 5-HT3/4 receptor-modulating agent, can directly affect collagen synthesis in vitro and attenuate experimentally induced fibrosis in vivo. Methods Functional in vitro studies were performed using human dermal fibroblasts (HDFs). Signal transduction studies included immunofluorescence analysis, Western immunoblotting, promoter reporter assays, cAMP/Ca2+ measurements, and use of pharmacologic activators and inhibitors. Gene silencing was performed using small interfering RNA. Putative receptors of tropisetron were detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. The murine model of bleomycin-induced scleroderma was used to assess the antifibrogenic and antifibrotic effects of tropisetron in vivo. Collagen expression in vitro, ex vivo, and in situ was determined by real-time RT-PCR analysis, Western immunoblotting, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunohistochemical analysis. Results Tropisetron suppressed collagen synthesis induced by transforming growth factor β1 (TGFβ1). This effect was independent of 5-HT3/4 receptor but was mediated via α7 nicotinic acetylcholine receptor (α7nAChR). Suppression of TGFβ1-induced collagen synthesis occurred via an unknown molecular mechanism not involving modulation of the Smad, cAMP, Akt, c-Jun, or MAPK pathway. In vivo, tropisetron not only prevented skin fibrosis but also reduced the collagen content in established dermal fibrosis induced by bleomycin. Conclusion Tropisetron directly reduces collagen synthesis in HDFs via an α7nAChR-dependent mechanism. The antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin- induced scleroderma indicate the future potential of tropisetron in the treatment of fibrotic diseases such as scleroderma. [ABSTRACT FROM AUTHOR]

Objective There is increasing evidence that serotonin (5-hydroxytryptamine [5-HT]) and distinct 5-HT receptors are involved in the pathogenesis of systemic sclerosis. The aim of this study was to test the hypothesis that tropisetron, a routinely used antiemetic agent previously characterized as a 5-HT3/4 receptor-modulating agent, can directly affect collagen synthesis in vitro and attenuate experimentally induced fibrosis in vivo. Methods Functional in vitro studies were performed using human dermal fibroblasts (HDFs). Signal transduction studies included immunofluorescence analysis, Western immunoblotting, promoter reporter assays, cAMP/Ca2+ measurements, and use of pharmacologic activators and inhibitors. Gene silencing was performed using small interfering RNA. Putative receptors of tropisetron were detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. The murine model of bleomycin-induced scleroderma was used to assess the antifibrogenic and antifibrotic effects of tropisetron in vivo. Collagen expression in vitro, ex vivo, and in situ was determined by real-time RT-PCR analysis, Western immunoblotting, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunohistochemical analysis. Results Tropisetron suppressed collagen synthesis induced by transforming growth factor β1 (TGFβ1). This effect was independent of 5-HT3/4 receptor but was mediated via α7 nicotinic acetylcholine receptor (α7nAChR). Suppression of TGFβ1-induced collagen synthesis occurred via an unknown molecular mechanism not involving modulation of the Smad, cAMP, Akt, c-Jun, or MAPK pathway. In vivo, tropisetron not only prevented skin fibrosis but also reduced the collagen content in established dermal fibrosis induced by bleomycin. Conclusion Tropisetron directly reduces collagen synthesis in HDFs via an α7nAChR-dependent mechanism. The antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin- induced scleroderma indicate the future potential of tropisetron in the treatment of fibrotic diseases such as scleroderma. [ABSTRACT FROM AUTHOR]

Neuropathic pain in animals results in increased IL-1β expression in the damaged nerve, the dorsal root ganglia, and the spinal cord. Here, we discuss our results showing that this cytokine is also overexpressed at supraspinal brain regions, in particular in the contralateral side of the hippocampus and prefrontal cortex and in the brainstem, in rats with neuropathic pain-like behavior. We show that neuropathic pain degree and development depend on the specific nerve injury model and rat strain studied, and that there is a correlation between hippocampal IL-1β expression and tactile sensitivity. Furthermore, the correlations between hippocampal IL-1β and IL-1ra or IL-6 observed in control animals, are disrupted in rats with increased pain sensitivity. The lateralization of increased cytokine expression indicates that this alteration may reflect nociception. The potential functional consequences of increased IL-1β expression in the brain during neuropathic pain are discussed. [ABSTRACT FROM AUTHOR]

We evaluated immune and endocrine status following antituberculosis treatment in HIV-negative patients with newly diagnosed tuberculosis (TB). Treatment led to a decrease in IL-6, IL-1β, and C-reactive protein levels. Cortisol levels decreased throughout the anti-TB treatment, particularly after 4 months, but changes were less pronounced than those seen in proinflammatory mediators. Specific therapy resulted in increased dehydroepiandrosterone (DHEA) levels, which peaked after 4 months and started to decline after 6 months of treatment, reaching levels below those detected at inclusion. In contrast, in most patients, dehydroepiandrosterone sulfate (DHEAS) levels remained unchanged, although a trend toward increased concentrations was observed in a few cases 3 months after the treatment was finished. Specific therapy also resulted in more balanced cortisol/DHEA and cortisol/DHEAS ratios. Etiologic treatment involves favorable immune and endocrine changes, which may account for its beneficial effects. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi infection in mice triggers neuroendocrine responses that affect the course of the disease. To analyze the contribution of adaptive immunity to these responses, comparative studies between normal C57Bl/6J and recombinase activator gene 1 (RAG-1)-deficient mice, which lack mature B and T lymphocytes, were performed. There was no difference between both types of mice in basal body weight. Following infection, higher parasitemia, increased IL-1β and IL-6 blood levels, less marked changes in lymphoid organs weight, no cardiomegaly, and earlier mortality were observed in RAG-1-deficient, compared with normal mice. The response of the hypothalamus-pituitary-adrenal axis after infection occurred earlier and was more intense in RAG-1-deficient mice than in normal mice. Noradrenaline concentration and serotonergic metabolism in the spleen, lymph nodes, and heart differed between RAG-1-deficient and normal mice. Our studies indicate that the absence of adaptive immunity to T. cruzi influences the neuroendocrine response to the infection with this parasite. [ABSTRACT FROM AUTHOR]

Supernatants (SN) from cultures of peripheral blood mononuclear cells (PBMC) of tuberculosis (TB) patients inhibit dehydroepiandrosterone (DHEA) secretion by the adrenal cell line NCI-H295R. To analyze whether TGF-β is involved in this effect, SN of PBMC from healthy controls or patients with severe TB infections, stimulated or not with Mycobacterium tuberculosis (Mtb SN), were added to adrenal cells under basal conditions or following stimulation with forskolin. Cortisol and DHEA concentrations were evaluated in supernatants of the adrenal cells cultured with or without the addition of anti-TGF-β. Treatment with Mtb SN from TB inhibited DHEA production, and this effect was reversed when SN were treated with anti-TGF-β. The increase in cortisol production induced by SN from TB patients was not affected by TGF-β neutralization. Mediators released during the anti-TB immune response differentially modulate steroid production by adrenal cells, and TGF-β is a cytokine implicated in the inhibition of DHEA production observed in TB. [ABSTRACT FROM AUTHOR]

Although aging is an inexorable component of life, its progress depends on how cumulative disruptions of homeostasis are compensated. Cumulative oxidative and inflammatory processes must be controlled to maintain successful aging. Heat shock proteins, such as those of the Hsp70 family, can be considered a danger signal, and their effects can either support longevity by neutralizing danger or can become detrimental when their production is not balanced. Here, we discuss evidence indicating that these highly conserved proteins can favor longevity when such balance is achieved. We emphasize mechanisms affected by Hsp72 that can interfere with effects of excessive oxidative stress and subtle inflammation and, acting either directly or by affecting neuro-immune-endocrine interactions, can mediate metabolic, neuroprotective, and behavioral adjustments during the aging process. [ABSTRACT FROM AUTHOR]

Interactions between T cells and noradrenergic pathways were investigated using athymic nude mice as a model. Higher noradrenaline (NA) concentrations and increased density of noradrenergic fibers were found in the spleen and hypothalamus, but not in the kidney, of 21-day-old Foxn1n (athymic) mice, compared with Foxn1n/Foxn1+ (heterozygous) littermates. Although no differences in nerve growth factor concentrations were detected, significantly higher brain-derived neurotrophic factor concentrations were found in the spleen and hypothalamus of athymic mice compared with the controls. All of these alterations were abrogated in Foxn1n mice reconstituted by thymus transplantation at birth. These results suggest that T lymphocytes or their products can induce (1) a decrease in the number and activity in splenic sympathetic nerve fibers; (2) a decrease in NA content in the hypothalamus, which, in turn, may influence the pituitary-adrenal axis and the descending neural pathways associated with the autonomic nervous system; and (3) changes in neurotrophin concentration in the spleen and hypothalamus. [ABSTRACT FROM AUTHOR]

Our study investigated the circulating levels of factors involved in immune-inflammatory-endocrine-metabolic responses in patients with tuberculosis with the aim of uncovering a relation between certain immune and hormonal patterns, their clinical status and in vitro immune response. The concentration of leptin, adiponectin, IL-6, IL-1β, ghrelin, C-reactive protein (CRP), cortisol and dehydroepiandrosterone (DHEA), and the in vitro immune response (lymphoproliferation and IFN-γ production) was evaluated in 53 patients with active untreated tuberculosis, 27 household contacts and 25 healthy controls, without significant age- or sex-related differences. Patients had a lower body mass index (BMI), reduced levels of leptin and DHEA, and increased concentrations of CRP, IL-6, cortisol, IL-1β and nearly significant adiponectin values than household contacts and controls. Within tuberculosis patients the BMI and leptin levels were positively correlated and decreased with increasing disease severity, whereas higher concentrations of IL-6, CRP, IL-1β, cortisol, and ghrelin were seen in cases with moderate to severe tuberculosis. Household contacts had lower DHEA and higher IL-6 levels than controls. Group classification by means of discriminant analysis and the k-nearest neighbor method showed that tuberculosis patients were clearly different from the other groups, having higher levels of CRP and lower DHEA concentration and BMI. Furthermore, plasma leptin levels were positively associated with the basal in vitro IFN-γ production and the ConA-driven proliferation of cells from tuberculosis patients. Present alterations in the communication between the neuro-endocrine and immune systems in tuberculosis may contribute to disease worsening. [ABSTRACT FROM AUTHOR]

The existence of a network of immunoneuroendocrine interactions that results in the reciprocal modulation of the classical functions of each system is well established at present. Most of the evidence derives from studies on secondary lymphoid organs, such as the spleen and lymph nodes. In this article, several aspects relevant to understand the role of the sympathetic nervous system in the establishment of these interactions in the thymus are discussed. At present, the sympathetic innervation of the thymus, the expression of adrenergic receptors in thymic cells, particularly of β-adrenergic receptors, and the effect of sympathetic neurotransmitters, although mainly derived from in vitro or pharmacological studies, seem to be relatively well studied. However, other aspects, such as the relevance that immune-sympathetic interactions at the thymic level may have for certain diseases, specially autoimmune or other diseases that primarily involve the activation of the immune system, as well as how the integration of sympathetic and hormonal signals at local levels may affect thymic functions, certainly deserve further investigation. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The immune system is a homeostatic system that contributes to maintain the constancy of the molecular and cellular components of the organism. Immune cells can detect the intrusion of foreign antigens or alteration of self-components and send information to the central nervous system (CNS) about this kind of perturbations, acting as a receptor sensorial organ. The brain can respond to such signals by emitting neuro/endocrine signals capable of affecting immune reactivity. Thus, the immune system, as other physiologic systems, is under brain control. Under disease conditions, when priorities for survival change, the immune system can, within defined limits, reset brain-integrated neuro-endocrine mechanisms in order to favour immune processes at the expenses of other physiologic systems. In addition, some cytokines initially conceived as immune products, such as IL-1 and IL-6, are also produced in the 'healthy' brain by glial cells and even by some neurons. These and other cytokines have the capacity to affect synaptic plasticity acting as mediators of interactions between astrocytes and pre- and post-synaptic neurons that constitute what is actually defined as a tripartite synapse. Since the production of cytokines in the brain is affected by peripheral immune and central neural signals, it is conceivable that tripartite synapses can, in turn, serve as a relay system in immune-CNS communication. [ABSTRACT FROM AUTHOR]

We studied whether, in parallel to the activity of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the development and chronification of arthritis induced by immunization of rats with type II collagen. Corticosterone levels were increased only transiently, and were even below the normal range as the disease progressed. Increased adrenaline blood levels and hypothalamic IL-1β and IL-6 overexpression were observed only during the induction phase of the disease. The increase in hypothalamic noradrenaline content during the symptomatic phase was paralleled by a gradual loss of sympathetic fibers in the joints. Depletion of hypothalamic noradrenergic neurons at this time did not affect the symptomatology. Contrary to observations in healthy animals, no correlation between hypothalamic IL-1β expression and noradrenaline content was observed in rats with arthritis. The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate that the communication between afferent immune messages to the central nervous system and two main efferent anti-inflammatory pathways under control of the brain are disrupted during experimental arthritis. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Wasting is a prominent feature in tuberculosis (TB), but its underlying mechanisms are incompletely understood. Immunoendocrine disturbances may be linked to the consumption state of TB patients, since hormones and cytokines can affect energy expenditure and metabolism. To approach this possibility, we have determined leptin, IL-18, and adrenal steroid plasma levels and body mass index (BMI) in newly diagnosed patients with mild, moderate and severe pulmonary TB, household contacts (HHC), and healthy controls (HCO). HHC displayed higher levels of leptin than HCO and TB patients. TB patients showed a gradual decrease in BMI and leptin concentrations with increasing disease severity, whereas a positive correlation between this hormone and BMI was found in the HCO group. Cortisol concentrations tended to be higher in TB patients. DHEA levels were decreased in TB patients and to a lesser extent in HHC, whereas IL-18 concentration was significantly increased in patients with severe disease. Since HHC are known to cause a latent subclinical infection, it seems clear that controlled tuberculous infection and manifested TB disease are accompanied by a dissimilar profile of immunoendocrine markers. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Earlier studies revealed that patients with tuberculosis (TB) have imbalanced immunoendocrine responses and that adrenal steroids [cortisol and dehydroepiandrosterone (DHEA)] can modify their specific cell-mediated immune response. Because most household contacts (HHCs) of contagious TB patients develop a subclinical and self-controlled process (latent TB), we studied some features of their immune and endocrine responses, particularly those related to the hypothalamic–pituitary–adrenal axis. Nineteen HHCs, 24 untreated TB patients (15 moderate, 9 advanced), and 18 healthy controls of similar age were studied. Patients had increased and reduced levels of cortisol and DHEA, respectively. DHEA levels were also reduced in HHCs. Stimulation of peripheral blood mononuclear cells (PBMC) with Mycobacterium tuberculosis sonicate resulted in increased in vitro lymphoproliferation in HHCs, while advanced patients showed the lowest response. Significantly higher amounts of interferon (IFN)-γ were detected in supernatants from stimulated PBMC of HHCs when compared to controls and TB patients. Addition of cortisol to the cultures inhibited mycobacterial antigen-driven IFN-γ production in all groups, although HHC supernatant contained significantly higher concentrations. In contrast, addition of DHEA to cultures of cells from HHCs resulted in increased IFN-γ levels. These results suggest the existence of a particular immunoendocrine relation assuring a preserved IFN-γ production in healthy housemates of TB patients. [ABSTRACT FROM AUTHOR]

The cytokine-mediated stimulation of the hypothalamus–pituitary–adrenal (HPA) axis is relevant for immunoregulation and survival during bacterial endotoxemia and certain viral infections. However, only limited information is available regarding the effect of endogenous glucocorticoids on parasitic diseases. Here, we discuss evidence that the increased levels of corticosterone that occur following Trypanosoma cruzi infection in mice is an endocrine response that protects the host by impeding an excessive production of pro-inflammatory cytokines. Comparative studies between susceptible C57Bl/6J and resistant Balb/c mice indicate that the predisposition to the disease depends on the appropriate timing and magnitude of the activation of the HPA axis. However, this endocrine response also results in thymus atrophy and depletion of CD4+CD8+ by apoptosis. On the other hand, using tumor necrosis factor (TNF)-receptor knockout mice, we found that TNF-α plays a complex role during this disease; it is involved in the mediation of cardiac tissue damage but it also contributes to prolonged survival. Taken together, this evidence indicates that a subtle balance between endocrine responses and cytokine production is necessary for an efficient defense against T. cruzi infection. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1β induces a prolonged hypoglycemia in mice that is not caused by a reduction in food intake and is dissociable from insulin effects. There is a peripheral component in the hypoglycemia that the cytokine induces resulting from an increased glucose uptake, an effect that can be exerted in a paracrine fashion at the site where IL-1 is locally produced. However, the maintenance of hypoglycemia is controlled at brain levels because the blockade of IL-1 receptors in the central nervous system inhibits this effect to a large extent. Furthermore, there is evidence that the cytokine interferes with counter regulation to hypoglycemia. Here we report that administration of IL-1 or long-lasting insulin results in different changes in food intake and in neuroendocrine mechanisms 8 h following induction of the same degree of hypoglycemia (40–45% decrease in glucose blood levels). Insulin, but not IL-1, caused an increase in food intake and an endocrine response that tends to reestablish euglycemia. Conversely, a decrease in noradrenergic and an increase in serotonergic activity in the hypothalamus occur in parallel with a reduction of glucose blood levels only in IL-1-treated mice, effects that can contribute to the maintenance of hypoglycemia. These results are compatible with the proposal that IL-1 acting in the brain can reset glucose homeostasis at a lower level. The biologic significance of this effect is discussed. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a chronic infectious disease accompanied by excessive and/or prolonged cytokine production, which might affect the immunoendocrine communication and favor the establishment of an adverse state with important alterations in essential biological functions. Studies in blood from TB patients showed increased levels of interferon γ (IFN-γ), interleukin 10 (IL-10), and IL-6, accompanied by a modest increase in the levels of cortisol, prolactin, and thyroid hormones and markedly augmented concentrations of growth hormone. Conversely, testosterone and dehydroepiandrosterone (DHEA) levels were profoundly decreased, resulting in an increased cortisol/DHEA ratio. The finding that culture supernatants from Mycobacterium-tuberculosis-stimulated peripheral blood mononuclear cells (PBMCs) of TB patients inhibit DHEA secretion by a human adrenal cell line indicates that immune cells from these patients can directly affect the synthesis of this hormone. Supporting the existence of bidirectional interactions, in vitro treatment of PBMCs from TB patients with physiological concentrations of cortisol inhibited mycobacterial antigen-driven lymphoproliferation and IFN-γ production, whereas DHEA suppressed transforming growth factor β production from cases with progressive disease. Further analysis showed that plasma DHEA levels correlated positively with the in vitroproduction of IFN-γ by mycobacterial-stimulated PBMCs, and the cortisol/DHEA ratio was inversely correlated with IFN-γ production. Lastly, it was also shown that the immunoendocrine imbalance in TB patients was associated with weight loss, which in turn correlated with the impairment on their specific in vitro cellular immune responses. These immunoendocrine interactions may play a detrimental role during TB, in terms of the development of protective immune responses, control of tissue damage and metabolic disorders, being implicated in disease aggravation and the ‘classic’ TB consumption. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents a study on the disruption of brain-immune system-joint communication during arthritis development stimulated by collagen II. The hypothalamic cytokine gene expression and neurotransmitter concentration, and joint innervation were assessed in Freund's incomplete adjuvant using laboratory rats. It concludes that communication is disrupted with the disassociation of hypothalamic cytokine gene expression, sympathetic signal loss, and nonadregenic neuronal activity.

With some exceptions, the sympathetic nervous system has often been regarded as an immunosuppressive system. However, we know now that the immunoregulatory role of the sympathetic nervous system cannot be described in such absolute terms. Indeed, sympathetic neurotransmitters can inhibit or stimulate an immune response depending on numerous variables, which include the type of adrenergic receptor involved, the kind of antigen that triggers the immune response, and the subset of immune cells affected. A most important consideration is that immune and sympathetic responses are phasic phenomena and the step of the immune response at which lymphoid and/or accessory cells are exposed to neurotransmitters, or deprived from their presence, seems decisive for the outcome. The large amount of basic research on the role that the sympathetic nervous system plays in neuroimmunomodulation has prompted studies on its pathological implications. Systemic lupus erythematosus is an autoimmune lymphoproliferative disease that has mainly been associated with a Th2 shift and increased humoral responses. Lpr/lpr mice, which express a defective Fas, are commonly used as a model of this disease, and more recently, also of the autoimmune lymphoproliferative syndrome. We have found that, besides defects in the Fas pathway, lpr/lpr mice have an altered sympathetic innervation, and that this alteration contributes to the pathogenesis of the disease. The results strongly support the hypothesis that the sympathetic nervous system can modulate the expression of autoimmune lymphoproliferative diseases. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

After saccharin intake is associated with the consequences of peripheral lipopolysaccharide (LPS) administration, rats develop a strong conditioned avoidance behavior against this gustatory stimulus. To investigate the role of central interleukin-1 (IL-1) as a key signal during taste-LPS engram formation, rats were chronically infused with IL-1 receptor antagonist into the lateral ventricle of the brain before, during and after a single association trial. The results indicate that a stable taste-LPS engram can be formed even under the chronic blockade of central IL-1 signaling during engram formation and consolidation. More importantly, our data show that animals which did not experience a fever response during association phase (due to the LPS encounter) were unable to elicit hyperthermia as part of the conditioned response. These data indicate that pairing a relevant taste stimulus with an immune challenge, such as LPS, might result in the formation of multiple engrams, specifically codifying independent information. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The study’s objective was to examine whether factors related to the host status may bear some relation with the profile of the immune response displayed by tuberculosis (TB) patients. The in vitro immune response (antigen-driven lymphoproliferation and cytokine production) and the presence of alcoholism or disease-related factors, like heart and respiratory rates, and weight loss (body mass index, BMI) were investigated in 31 males with active, untreated TB. Compared to 16 age-matched healthy males, TB patients presented depressed lymphoproliferation and increased IL-10 and TGF-β production. Multivariate analysis indicated that most differences were no longer significant when controlling for the BMI. Immune and endocrine changes coexisting with weight loss, such as circulating levels of TNF-α, IFN-γ, IL-6, cortisol, dehydroepiandrosterone and thyroid hormones, were also analyzed. While pairwise correlations between serum levels of IFN-γ, T3 or T4 and BMI were not significant, BMI was negatively correlated with IL-6 levels (p < 0.025). In turn, levels of IL-6 correlated positively with cortisol concentrations (p <0.001). Stepwise regression analysis demonstrated that BMI was only associated with IL-6 (r = –0.423, R2 = 0.18), with the difference remaining significant following adjustment for the other variables. As regards IL-6, BMI, cortisol and IFN-γ could explain 74% of variability in IL-6 concentrations (R2 = 0.74). No evidence for effect modification was shown when performing adjusted calculations. To conclude, the relation between weight loss and abnormal immune response of TB patients is partly associated with the immunoendocrine imbalance observed in parallel. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Administration of IL-1β results in a profound and long-lasting hypoglycemia. Here, we show that this effect can be elicited by endogenous IL-1 and is related to not only the capacity of the cytokine to increase glucose uptake in peripheral tissues but also to mechanisms integrated in the brain. We show that (i) blockade of IL-1 receptors in the brain partially counteracted IL-1-induced hypoglycemia; (ii) peripheral administration or induction of IL-1 production resulted in IL-1β gene expression in the hypothalamus of normal and insulin-resistant, leptin receptor-deficient, diabetic db/db mice; (iii) IL-1-treated normal and db/db mice challenged with glucose did not return to their initial glucose levels but remained hypoglycemic for several hours. This effect was largely antagonized by blockade of IL-1 receptors in the brain; and (iv) when animals with an advanced Type II diabetes were treated with IL-1 and challenged with glucose, they died in hypoglycemia. However, when IL-1 receptors in the brains of these diabetic mice were blocked, they survived, and glucose blood levels approached those that these mice had before II.-1 administration. The prolonged hypoglycemic effect of IL-1 is insulin-independent and develops against increased levels of glucocorticoids, catecholamines, and glucagon. These findings, together with the present demonstration that this effect is integrated in the brain and is paralleled by IL-1β expression in the hypothalamus, indicate that this cytokine can reset glucose homeostasis at central levels. Such reset, along with the peripheral actions of the cytokine, would favor glucose uptake by immune cells during inflammatory/immune processes. [ABSTRACT FROM AUTHOR]

The interleukin-1 (IL-1) cytokine family (IL-1α, IL-β, and the IL-1 receptor antagonist) is involved in immune and inflammatory responses both in the brain and in the periphery. Recently, it has also been shown to influence behavior and memory consolidation. However, within the experimental systems studied, it has remained unclear whether the role of IL-1β is associated solely with a pathophysiological process or whether it is a neuromodulator in normal adult brain. To evaluate the involvement of the nonpathological endogenous IL-1 system in learning, we studied the expression of IL-1α, IL-1β, and IL-1ra during memory consolidation. We observed a learning-specific hippocampal IL-1α mRNA induction, but not that of IL-1β or IL-1ra mRNAs, after inhibitory avoidance training. Moreover, when IL-1 receptor activity was inhibited using an adenoviral vector that expresses the IL-1 receptor antagonist (IL-1ra) in the hippocampus, both short-term and long-term memory retention scores were facilitated. In contrast, endogenous hippocampal IL-1 played no role in the habituation to a novel environment. These results demonstrate that endogenous hippocampal IL-1 specifically modulates a fear-motivated learning task, and suggest that IL-1α activity in the CNS is part of the hippocampal memory processing. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Microglial activation has been associated with the pathogenesis of Parkinson's disease (PD). Among the many components of this reaction, cytokines have been proposed as candidates to mediate neurodegenerative or neuroprotective effects. We investigated the interleukin-1 system and tumour necrosis factor-α mRNA and protein levels at different time intervals in the subacute intrastriatal 6-hydroxydopamine rat model of PD, in parallel with the inflammatory response. Immunohistochemistry showed that microglial cells were activated from days 6–30 postlesion in the substantia nigra pars compacta. This microglial activation was accompanied by an atypical proinflammatory cytokine production: Interleukin-1α and β mRNAs were found to be elevated 30 days post-6-hydroxydopamine injection (2- and 16-fold, respectively), but no induction for interleukin-1α or β at the protein level was detected by ELISA. As a control, a classical proinflammatory stimulus, namely endotoxin, was capable of inducing these cytokines at similar mRNA levels but also at the protein level. In addition, tumour necrosis factor-α mRNA was hardly or not detected in the substantia nigra at any time point studied. Our data point out a tight control of key proinflammatory cytokine production in our model of PD. This work supports the notion that chronic neuronal death per se does not induce secretion of these proinflammatory cytokines but that an additional stimulus is necessary to stimulate proinflammatory cytokine production. The production of proinflammatory cytokines from “primed” microglia may in turn modulate disease progression as has been recently proposed in a model of prion disease. [ABSTRACT FROM AUTHOR]

Abstract Experimental and clinical evidence has demonstrated extensive communication between the CNS and the immune system. To analyse the role of central catecholamines in modulating peripheral immune functions, we injected the neurotoxin 6-hydroxydopamine (6-OHDA) i.c.v. in rats. This treatment significantly reduced brain catecholamine content 2, 4 and 7 days after injection, and in the periphery splenic catecholamine levels were reduced 4 days after treatment. Central catecholamine depletion induced an inhibition of splenic and blood lymphocyte proliferation and splenic cytokine production and expression (interleukin-2 and interferon-γ) 7 days after injection. In addition, central treatment with 6-OHDA reduced the percentage of spleen and peripheral blood natural killer (CD161 +) cells, and T-cytotoxic (CD8 +) cells in peripheral blood. The reduction in splenocyte proliferation was not associated with a glucocorticoid alteration but was completely abolished by prior peripheral sympathectomy. These data demonstrate a crucial role of central and peripheral catecholamines in modulating immune function. [ABSTRACT FROM AUTHOR]

Studies the influence of increased splenic vascular perfusion induced by either local denervation or general sympathectomy on lymphoid cell uptake by the spleen and endotoxin-stimulated rats. Increased retention of cells in the spleen paralleled by increased blood flow; Redistribution of blood perfusion during general vasolidation.

Background Sp4 is a zinc finger transcription factor which is closely related to Sp1 and Sp3. All three proteins recognize the same DNA elements and can act as transcriptional activators through glutamine-rich activation domains. Unlike Sp1 and Sp3, which are ubiquitous proteins, Sp4 is highly abundant in the central nervous system, but also detectable in many other tissues. Results We have disrupted the mouse Sp4 gene by a targeted deletion of the exons encoding the N-terminal activation domains. Sp4 knockout mice show a complete absence of Sp4 expression. They develop until birth without obvious abnormalities. After birth, two-thirds die within 4 weeks. Surviving mice are growth retarded. Male Sp4null mice do not breed. The cause for the breeding defect remains obscure since they show complete spermatogenesis. In addition, pheromone receptor genes in the vomeronasal organ appear unaffected. Female Sp4null mice have a smaller thymus, spleen and uterus. In addition, they exhibit a pronounced delay in sexual maturation. Conclusions The phenotype of the Sp4null mice differs significantly from those described for Sp1–/– and Sp3–/– mice. Thus, the structural similarities, the common recognition motif and the overlapping expression pattern of these three transcription factors do not reflect similar physiological functions. [ABSTRACT FROM AUTHOR]