Marburg an der Lahn, Germany
Marburg an der Lahn, Germany

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Ortega E.,University of Extremadura | Bote M.E.,University of Extremadura | Besedovsky H.O.,Institute of Physiology and Pathophysiology | Rey A.D.,Institute of Physiology and Pathophysiology
Annals of the New York Academy of Sciences | Year: 2012

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. © 2012 New York Academy of Sciences.


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.


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.


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


Del Rey A.,Institute of Physiology and Pathophysiology | Yau H.-J.,Northwestern University | Randolf A.,Institute of Physiology and Pathophysiology | Centeno M.V.,Northwestern University | And 4 more authors.
Pain | Year: 2011

We have proposed that neuropathic pain engages emotional learning, suggesting the involvement of the hippocampus. Because cytokines in the periphery contribute to induction and maintenance of neuropathic pain but might also participate centrally, we used 2 neuropathic pain models, chronic constriction injury (CCI) and spared nerve injury (SNI), to investigate the temporal profile of hippocampal cytokine gene expression in 2 rat strains that show different postinjury behavioral threshold sensitivities. SNI induced long-lasting allodynia in both strains, while CCI induced allodynia with time-dependent recovery in Sprague Dawley (SD) and no allodynia in Wistar Kyoto (WK) rats. In WK rats, only SNI induced sustained upregulation of hippocampal interleukin (IL)-1β, while IL-6 expression was transiently increased and no significant changes in IL-1ra expression were detected. Conversely, in SD rats, SNI resulted in sustained and robust increased hippocampal IL-1β expression, which was only transient in rats with CCI. In this strain, IL-6 expression was not affected in any of the 2 injury models and IL-1ra expression was significantly increased in rats with SNI or CCI at late phases. We found that the degree and development of neuropathic pain depend on the specific nerve injury model and rat strain; that hippocampal IL-1β mRNA levels correlate with neuropathic pain behavior; that, in contrast to sham-operated animals, there are no correlations between hippocampal IL-1β and IL-1ra or IL-6 in neuropathic rats; and that alterations in cytokine expression are restricted to the hippocampus contralateral to the injury side, again implying that the observed changes reflect nociception. © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


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.


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.


Thevenod F.,Institute of Physiology and Pathophysiology | Lee W.-K.,Institute of Physiology and Pathophysiology
Metal Ions in Life Sciences | Year: 2013

The detrimental health effects of cadmium (Cd) were first described in the mid 19th century. As part of industrial developments, increasing usage of Cd has led to widespread contamination of the environment that threatens human health, particularly today. Rather than acute, lethal exposures, the real challenge in the 21st century in a global setting seems to be chronic low Cd exposure (CLCE), mainly from dietary sources. Ubiquity of Cd makes it a serious environmental health problem that needs to be thoroughly assessed because it already affects or will affect large proportions of the world's population. CLCE is a health problem that affects increasingly organ toxicity, especially nephrotoxicity, without a known threshold, implying that there is currently no safe limit for CLCE. In this chapter, we summarize current knowledge on the sources of Cd in the environment, describe the entry pathways for Cd into mammalian organisms, sum up the major organs targeted by acute or chronic Cd exposure and review the impact of Cd on organ function and human health. We also aim to put early pioneering studies on Cd poisoning into perspective in the context of recent ground-breaking prospective long-term population studies, which link CLCE to leading causes of diseases in modern societies - cancer, diabetes, and cardiovascular diseases, and of state-of-the-art studies detailing cellular and molecular mechanisms of acute and chronic Cd toxicity. © Springer Science+Business Media Dordrecht 2013.


Besedovsky H.O.,Institute of Physiology and Pathophysiology | Del Rey A.,Institute of Physiology and Pathophysiology
NeuroImmunoModulation | Year: 2010

We briefly discuss here evidence showing that the capacity of IL-1β to mediate adjustments of glucose homeostasis can be added to the already well-known pleiotropic effects of this cytokine. Such adjustments, which are necessary for satisfying the high energetic demands of immune/inflammatory responses, can be mediated by effects of endogenous IL-1 exerted at peripheral and brain levels in a concerted action with other cytokines and neuroendocrine mechanisms. © 2010 S. Karger AG, Basel.


Hainke S.,Institute of Physiology and Pathophysiology | Wildmann J.,Institute of Physiology and Pathophysiology | Del Rey A.,Institute of Physiology and Pathophysiology
International Immunopharmacology | Year: 2015

The existence of interactions between the immune and the sympathetic nervous systems is well established. Noradrenaline can promote or inhibit the immune response, and conversely, the immune response itself can affect noradrenaline concentration in lymphoid organs, such as the spleen. It is also well known that acetylcholine released by pre-ganglionic neurons can modulate noradrenaline release by the postsynaptic neuron. The spleen does not receive cholinergic innervation, but it has been reported that lymphocytes themselves can produce acetylcholine, and express acetylcholine receptors and acetylcholinesterase. We found that the spleen of not overtly immunized mice in which muscarinic type 1 acetylcholine receptors have been knocked out (M1KO) has higher noradrenaline concentrations than that of the wildtype mice, without comparable alterations in the heart, in parallel to a decreased number of IgG-producing B cells. Splenic lymphocytes from M1KO mice displayed increased in vitro-induced cytotoxicity, and this was observed only when CD4+ T cells were present. In contrast, heterozygous acetylcholinesterase (AChE +/-) mice, had no alterations in splenic noradrenaline concentration, but the in vitro proliferation of AChE +/- CD4+ T cells was increased. It is theoretically conceivable that reciprocal effects between neuronally and non-neuronally derived acetylcholine and noradrenaline might contribute to the results reported. Our results emphasize the need to consider the balance between the effects of these mediators for the final immunoregulatory outcome. © 2015 Elsevier B.V. All rights reserved.

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