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Marburg an der Lahn, Germany

del Rey A.,Institute of Physiology and Pathophysiology
Molecular Psychiatry | Year: 2015

It is still controversial which mediators regulate energy provision to activated neural cells, as insulin does in peripheral tissues. Interleukin-1β (IL-1β) may mediate this effect as it can affect glucoregulation, it is overexpressed in the ‘healthy’ brain during increased neuronal activity, and it supports high-energy demanding processes such as long-term potentiation, memory and learning. Furthermore, the absence of sustained neuroendocrine and behavioral counterregulation suggests that brain glucose-sensing neurons do not perceive IL-1β-induced hypoglycemia. Here, we show that IL-1β adjusts glucoregulation by inducing its own production in the brain, and that IL-1β-induced hypoglycemia is myeloid differentiation primary response 88 protein (MyD88)-dependent and only partially counteracted by Kir6.2-mediated sensing signaling. Furthermore, we found that, opposite to insulin, IL-1β stimulates brain metabolism. This effect is absent in MyD88-deficient mice, which have neurobehavioral alterations associated to disorders in glucose homeostasis, as during several psychiatric diseases. IL-1β effects on brain metabolism are most likely maintained by IL-1β auto-induction and may reflect a compensatory increase in fuel supply to neural cells. We explore this possibility by directly blocking IL-1 receptors in neural cells. The results showed that, in an activity-dependent and paracrine/autocrine manner, endogenous IL-1 produced by neurons and astrocytes facilitates glucose uptake by these cells. This effect is exacerbated following glutamatergic stimulation and can be passively transferred between cell types. We conclude that the capacity of IL-1β to provide fuel to neural cells underlies its physiological effects on glucoregulation, synaptic plasticity, learning and memory. However, deregulation of IL-1β production could contribute to the alterations in brain glucose metabolism that are detected in several neurologic and psychiatric diseases.Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.174. © 2015 Macmillan Publishers Limited Source

del Rey A.,Institute of Physiology and Pathophysiology | Apkarian A.V.,Northwestern University | Martina M.,Northwestern University | Besedovsky H.O.,Institute of Physiology and Pathophysiology
Annals of the New York Academy of Sciences | Year: 2012

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. © 2012 New York Academy of Sciences. Source

Besedovsky H.O.,Institute of Physiology and Pathophysiology | Del Rey A.,Institute of Physiology and Pathophysiology
Current Pharmaceutical Design | Year: 2014

Pleiotropic effects, great potency, and the capacity to induce its own production are distinguishing characteristics of IL-1. Among the multiple physiological effects of this cytokine, we emphasize here its role in supporting immune processes by stimulating most immune cells, and in re-setting glucose homeostasis. These aspects are complementary because stimulatory actions of IL-1 may be due to its capacity to increase glucose uptake by immune cells in the periphery and to affect the control of glucose homeostasis at brain levels, so as to deviate this main fuel to immune cells during inflammatory and infectious diseases. Thus, IL-1 can contribute to maintain a lean phenotype, inhibit food intake, and exert hypoglycemic effects. However, these effects of IL-1 can be overridden particularly when it is overproduced ectopically in other tissues, as it occurs during the autoimmune process that destroys the pancreas and causes type 1 diabetes, or when obesity triggers its production in adipose tissue and influences the development of type 2 diabetes. During obesity, products of enlarged adipocytes, e.g. fatty acids, are sensed as danger signals by infiltrating immune cells and, together with hypoxia, results in an ectopic overproduction of IL-1 that is largely mediated by activation of the NLRP3-caspase-1 inflammasome. Insulin and leptin resistance develops by mutual IL-1β-TNFα induction, and hyperglycemia causes ectopic production of IL-1 in the pancreas, which deregulates insulin production and favors the development of type 2 diabetes. In conclusion, whether IL-1 exerts physiologic or pathologic effects depends on its amount and on the spatial and temporal pattern of its production. © 2014 Bentham Science Publishers. Source

Besedovsky H.O.,Institute of Physiology and Pathophysiology | Del Rey A.,Institute of Physiology and Pathophysiology
Neurochemical Research | Year: 2011

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. © 2010 Springer Science+Business Media, LLC. Source

Santucci N.,National University of Rosario | D'Attilio L.,National University of Rosario | Kovalevski L.,National University of Rosario | Bozza V.,National University of Rosario | And 4 more authors.
PLoS ONE | Year: 2011

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. © 2011 Santucci et al. Source

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