Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a Th2 polarization.

Neuropeptide Y (NPY), a major autonomic nervous system and stress mediator, is emerging as an important regulator of inflammation, implicated in autoimmunity, asthma, atherosclerosis, and cancer. Yet the role of NPY in regulating phenotype and functions of dendritic cells (DCs), the professional antigen-presenting cells, remains undefined. Here we investigated whether NPY could induce DCs to migrate, mature, and polarize naive T lymphocytes. We found that NPY induced a dose-dependent migration of human monocyte-derived immature DCs through the engagement of NPY Y1 receptor and the activation of ERK and p38 mitogen-activated protein kinases. NPY promoted DC adhesion to endothelial cells and transendothelial migration. It failed to induce phenotypic DC maturation, whereas it conferred a T helper 2 (Th2) polarizing profile to DCs through the up-regulation of interleukin (IL)-6 and IL-10 production. Thus, during an immune/inflammatory response NPY may exert proinflammatory effects through the recruitment of immature DCs, but it may exert antiinflammatory effects by promoting a Th2 polarization. Locally, at inflammatory sites, cell recruitment could be amplified in conditions of intense acute, chronic, or cold stress. Thus, altered or amplified signaling through the NPY-NPY-Y1 receptor-DC axis may have implications for the development of inflammatory conditions.-Buttari, B., Profumo, E., Domenici, G., Tagliani, A., Ippoliti, F., Bonini, S., Businaro, R., Elenkov, I., Riganò, R. Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a Th2 polarization.

Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans?

Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual's neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary "defect" related to specific neurohormonal immune phenotype(s). We report that in a large subpopulation of healthy humans the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS ex vivo. In alternative settings, we found low baseline levels and profoundly blunted stress-induced epinephrine responses but high TNF-alpha levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a beta adrenoreceptor agonist suppressed LPS-induced TNF-alpha production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the beta(2) adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-alpha and IL-12, but stimulated IL-10 production. The order of potency for hormones able to inhibit IL-12 production ex vivo was: epinephrine > norepinephrine > or = 1,25-(OH)(2) vitamin D(3) > hydrocortisone. This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles. Since Lewis and Fischer rats have opposite susceptibility to experimental immunological diseases, this suggests that the parallel human phenotypes could be linked to differing responsiveness and susceptibility to infections and immune/inflammatory-related conditions.

Immunohistochemical profile of neurotrophins in human cranial dura mater and meningiomas.

The immunohistochemical profile of neurotrophins and their receptors in the human cranial dura mater was studied by examining certain dural zones in specimens harvested from different regions (frontal, temporal, parietal and occipital). Dural specimens were obtained during neurosurgical operations performed in ten patients for surgical treatment of intracranial lesions (meningiomas, traumas, gliomas, vascular malformations). The dural fragments were taken from the area of the craniotomy at least 8 cm from the lesion as well as from the area in which the meningioma had its dural attachment. Immunohistochemical characterization and distribution of neurotrophins, with their receptors, were analyzed. The concrete role played by these neurotrophic factors in general regulation, vascular permeability, algic responsivity and release of locally active substances in the human dura mater is still controversial. Our study revealed a general structural alteration of dural tissue due to the invasivity of meningiomatous lesions, together with an improved expression of brain derived neurotrophic factor (BDNF) in highly proliferating neoplastic cells and an evident production of nerve growth factor (NGF) in inflammatory cells, suggesting that BDNF has a role in supporting the proliferation rate of neoplastic cells, while NGF is involved in the activation of a chronic inflammatory response in neoplastic areas.

Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being.

The neuroendocrine system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions, such as antigen presentation, antibody production, lymphocyte activity, proliferation and traffic, and the secretion of cytokines including the selection of T helper (Th)1 or Th2 cytokine responses. During inflammation, the activation of the stress system, through induction of a Th2 shift protects the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones, substance P, ATP and the activation of the corticotropin-releasing hormone/substance P-histamine axis may actually facilitate inflammation, through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor (TNF)-alpha and CRP production. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression and atherosclerosis. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

Psychoneuroimmunology.

Psychoneuroimmunology (PNI) is a discipline that has evolved in the last 40 years to study the relationship between immunity, the endocrine system, and the central and peripheral nervous systems. In this manner, neurotransmitters, hormones, and neuropeptides have been found to regulate immune cells, and these in turn are capable of communicating with nervous tissue through the secretion of a wide variety of cytokines. Of critical importance is the effect of products of the CNS and nerves on the maintenance of the delicate balance between cell-mediated (Th1) and humoral (Th2) immune responses. A good example of how this concept operates in vivo becomes evident when analyzing the effects of stressors. Chronic stress affects significantly the function of the immune system as well as modifies the evolution of a variety of skin diseases, as psychosocial interventions have proved to be effective in their therapy.

Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases.

Associations between stress and health outcomes have now been carefully documented, but the mechanisms by which stress specifically influences disease susceptibility and outcome remain poorly understood. Recent evidence indicates that glucocorticoids (GCs) and catecholamines (CAs), the major stress hormones, inhibit systemically IL-12, TNF-alpha, and INF-gamma, but upregulate IL-10, IL-4, and TGF-beta production. Thus, during an immune and inflammatory response, the activation of the stress system, through induction of a Th2 shift may protect the organism from systemic "overshooting" with T helper lymphocyte 1 (Th1)/proinflammatory cytokines. In certain local responses and under certain conditions, however, stress hormones may actually facilitate inflammation, through induction of IL-1, IL-6, IL-8, IL-18, TNF-alpha, and CRP production, and through activation of the corticotropin-releasing hormone (CRH)/substance P(SP)-histamine axis. Autoimmunity, chronic infections, major depression, and atherosclerosis are characterized by a dysregulation of the pro/anti-inflammatory and Th1/Th2 cytokine balance. Thus, hyperactive or hypoactive stress system, and a dysfunctional neuroendocrine-immune interface associated with abnormalities of the "systemic anti-inflammatory feedback" and/or "hyperactivity" of the local proinflammatory factors may contribute to the pathogenesis of these diseases. Conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, pregnancy and the postpartum period, or rheumatoid arthritis (RA) through modulation of the systemic or local pro/anti-inflammatory and Th1/Th2 cytokine balance, may suppress or potentiate disease activity and/or progression. Thus, stress hormones-induced inhibition or upregulation of innate and Th cytokine production may represent an important mechanism by which stress affects disease susceptibility, activity, and outcome of various immune-related diseases.

Glucocorticoids and the Th1/Th2 balance.

Evidence accumulated over the last 5-10 years indicates that glucocorticoids (GCs) inhibit the production of interleukin (IL)-12, interferon (IFN)-gamma, IFN-alpha, and tumor necrosis factor (TNF)-alpha by antigen-presenting cells (APCs) and T helper (Th)1 cells, but upregulate the production of IL-4, IL-10, and IL-13 by Th2 cells. Through this mechanism increased levels of GCs may systemically cause a selective suppression of the Th1-cellular immunity axis, and a shift toward Th2-mediated humoral immunity, rather than generalized immunosuppression. During an immune response and inflammation, the activation of the stress system, and thus increased levels of systemic GCs through induction of a Th2 shift, may actually protect the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines and other products of activated macrophages with tissue-damaging potential. However, conditions associated with significant changes of GCs levels, such as acute or chronic stress or cessation of chronic stress, severe exercise, and pregnancy and postpartum, through modulation of the Th1/Th2 balance may affect the susceptibility to or the course of infections as well as autoimmune and atopic/allergic diseases.

Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity.

Recent evidence indicates that glucocorticoids and catecholamines, the major stress hormones, inhibit the production of proinflammatory cytokines, such as interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, whereas they stimulate the production of antiinflammatory cytokines, such as IL-10, IL-4, and transforming growth factor (TGF)-beta. Thus, systemically, an excessive immune response, through activation of the stress system, stimulates an important negative feedback mechanism, which protects the organism from an "overshoot" of proinflammatory cytokines and other products of activated macrophages with tissue-damaging potential. Conversely, in certain local responses and under certain conditions, stress hormones actually may boost regional immune responses, through induction of TNF-alpha, IL-1, and IL-8, and by inhibiting TGF-beta production. Therefore, conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, severe exercise, and pregnancy and the postpartum period, through modulation of the systemic or local pro/antiinflammatory cytokine balance, may suppress or potentiate autoimmune diseases activity and/or progression.

Stress system--organization, physiology and immunoregulation.

Stress is defined as a state of threatened homeostasis. The principal effectors of the stress system include corticotropin-releasing hormone, arginine vasopressin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Activation of the stress system leads to adaptive behavioral and physical changes. The principal stress hormones glucocorticoids and catecholamines affect major immune functions such as antigen presentation, leukocyte proliferation and traffic, secretion of cytokines and antibodies, and selection of the T helper (Th) 1 versus Th2 responses. A fully fledged systemic inflammatory reaction results in stimulation of the stress response, which in turn, through induction of a Th2 shift protects the organism from systemic overshooting with Th1/pro-inflammatory cytokines. Stress is often regarded as immunosuppressive, but recent evidence indicates that stress hormones influence the immune response in a less monochromatic way--systemically they inhibit Th1/pro-inflammatory responses and induce a Th2 shift, whereas in certain local responses they promote pro-inflammatory cytokine production and activation of the corticotropin-releasing hormone-mast cell-histamine axis. Through this mechanism a hyper- or hypoactive stress system associated with abnormalities of the systemic anti-inflammatory feedback and/or hyperactivity of the local pro-inflammatory factors may play a role in the pathogenesis of chronic inflammation and immune-related diseases.

Cytokine dysregulation, inflammation and well-being.

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action: potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection.

The HIV-1 protein Vpr has glucocorticoid receptor coactivator activity, potently increasing the sensitivity of glucocorticoid target tissues to cortisol. Patients with AIDS and normal cortisol secretion have manifestations compatible with glucocorticoid hypersensitivity of the immune system, such as suppression of innate and cellular immunities. The latter can be explained by glucocorticoid-induced inhibition of cytokine networks regulating innate and Th1-driven cellular immunity. We demonstrated that extracellularly administered Vpr protein dose-dependently potentiated glucocorticoid-induced suppression of both mRNA expression and secretion of IL-12 subunit p35 and IL-12 holo-protein, but not IL-12 subunit p40 or IL-10, by human monocytes/macrophages stimulated with LPS or heat-killed, formalin-fixed Staphylococcus aureus (Cowan strain 1). This effect was inhibited by the glucocorticoid receptor antagonist RU 486. Also, Vpr changed the expression of an additional five glucocorticoid-responsive genes in the same direction as dexamethasone and was active in potentiating the trans-activation, but not the trans-repression, properties of the glucocorticoid receptor on nuclear factor kappaB- or activating protein 1-regulated simple promoters. Thus, extracellular Vpr enhances the suppressive actions of the ligand-activated glucocorticoid receptor on IL-12 secretion by human monocytes/macrophages. Through this effect, Vpr may contribute to the suppression of innate and cellular immunities of HIV-1-infected individuals and AIDS patients.