Adriana del Rey

Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease.

Microglial activation has been associated with the pathogenesis of Parkinsons 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.

Interleukin-1 induces changes in norepinephrine metabolism in the rat brain ☆

Interleukin-1 (IL-1) is a hormone that, apart from playing a key role in immune and inflammatory processes, can also affect mechanisms under brain control. To gain a better understanding of the action of this cytokine on the CNS, its effects on the contents of norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their main metabolites and precursors, were evaluated in different regions of the forebrain, brain stem, and spinal cord. Following administration of human recombinant IL-1 (beta form) to rats, a modest decrease in the content of NE was observed in the hypothalamus as well as in the dorsal posterior brain stem. However, the most relevant finding was that 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the main NE metabolite, and the relation MHPG/NE were increased in all the regions studied, revealing a stimulatory effect of IL-1 on NE metabolism in the CNS. This effect seems to be specific for NE since no comparable changes in the brain content of DA, 5-HT, or its metabolite, 5-hydroxyindole acetic acid, were detected after administration of the cytokine. However, tryptophan was significantly increased in all brain regions and in the cervical spinal cord. The capacity of IL-1 to affect the metabolism of NE, a neurotransmitter involved in the control of a variety of brain functions, provides further proof for the relevance of this cytokine in brain-immune interactions.

Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice

The regional distribution and inducibility of cytokines in the normal brain is still a matter of controversy. As an attempt to clarify this issue, we studied the constitutive and induced expression of interleukin (IL)‐1β, IL‐6, tumor necrosis factor (TNF)‐α, and interferon (IFN)‐γ mRNAs in the brain, pituitary, and spleen of mice using qualitative and semiquantitative reverse‐transcription polymerase chain reaction. The contribution of nonbrain cells to the cytokine transcripts detected was considered. With the exception of IFN‐γ mRNA, transcripts for the other cytokines were found to be constitutively present in the brain. Following i.p. injection of lipopolysaccharide (LPS) at a dose below those described to disrupt the blood‐brain barrier (BBB), cytokine mRNA expression was increased in the spleen, the pituitary, and the brain. In the brain, the onset of transcription varied from 45 min (IL‐1β, TNF‐α) to 4 hr (IFN‐γ), and the peak of mRNA accumulation was observed at different times depending on the cytokine and the brain region studied. IL‐1 and IL‐6 were highly expressed in the hypothalamus and hippocampus, while TNF‐α expression was more marked in the thalamus‐striatum. The cortex was the region in which cytokines were less inducible. The inducible expression of cytokine mRNAs in the brain was paralleled by stimulation of hypothalamus‐pituitary‐adrenal axis. These results show the capacity of brain cells to synthesize different cytokine mRNAs in vivo and define the kinetics of their expression in several brain areas and in the periphery in parallel to the activation of a neuroendocrine pathway by endotoxin. J. Neurosci. Res. 48:287–298, 1997.

Neuroendocrine, sympathetic and metabolic responses induced by interleukin-1

Effects on turnover of vasopressin (AVP) in the hypothalamus and on secretion of pituitary hormones, catecholamines and insulin after intraperitoneal injection of recombinant interleukin-1 (beta) (IL-1) were investigated in male wistar rats. Intraperitoneal administration of IL-1 in a dose (1 microgram) that maximally activated pituitary-adrenal activity failed to alter plasma concentrations of prolactin, luteinizing hormone and melanocyte-stimulating hormone. Rats chronically cannulated in the right jugular veins showed a time-related increase in plasma corticosterone concentrations in response to intraperitoneal administration of IL-1 that lasted up to 4 h. In the same rats, plasma epinephrine (E) and norepinephrine (NE) concentrations were only slightly elevated (2-fold increase) at 30 min and at 1 h after IL-1 administration. Unlike in endotoxin-resistant C3H/HeJ mice, where IL-1 induces hypoglycemia, IL-1 did not affect plasma concentrations of glucose and insulin in Wistar rats. In the zona externa of the median eminence, IL-1 stimulated corticotropin-releasing factor (CRF) turnover at an approximate rate of 15%/h, but did not cause a concomitant change in AVP turnover as can be observed after insulin-induced hypoglycemia. Since half of the hypothalamic CRF neurons have been shown to costore AVP, the data favor the view of a selective effect of IL-1 on a subtype of CRF neurons. We conclude that pituitary-adrenal activation in response to Il-1 is caused by CRF secretion from a subtype of CRF neurons (not storing AVP) in the rat hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiology of psychoneuroimmunology : A personal view

This article offers a personal view on how the concept of the existence of a network of immune-neuro-endocrine interactions has evolved in the last 30 years. The main topic addressed is the relevance of the exchange of signals between the immune, endocrine and nervous systems for immunoregulation and brain functions. Particular emphasis is given to circuits involving immune cell products, the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. The operation of these circuits can affect immune functions and the course of inflammatory, autoimmune and infectious diseases. We also discuss increasing evidence that brain-born cytokines play an important role in brain physiology and in the integration of the immune-neuro-endocrine network.

Expression of IL-1β in supraspinal brain regions in rats with neuropathic pain

We examined mRNA expression of the pro-inflammatory cytokine IL-1beta in the brainstem, thalamus, and prefrontal cortex in two rat models of neuropathic pain. Rats received a neuropathic injury: spared nerve injury (SNI) or chronic constriction injury (CCI), sham injury, or were minimally handled (control). Neuropathic pain-like behavior was monitored by tracking tactile thresholds. SNI-injured animals showed a robust decrease in tactile thresholds of the injured foot, while CCI-injured animals did not show tactile threshold changes. Ten or 24 days after nerve injury, IL-1beta gene expression in the brain was determined by RT-PCR. IL-1beta expression changes were observed mainly at 10 days after injury in the SNI animals, contralateral to the injury side, with increased expression in the brainstem and prefrontal cortex. The results indicate that neuro-immune activation in neuropathic pain conditions includes supraspinal brain regions, suggesting cytokine modulation of supraspinal circuitry of pain in neuropathic conditions.

A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning

We have previously shown that long-term potentiation (LTP) induces hippocampal IL-1β and IL-6 over-expression, and interfering their signalling either inhibits or supports, respectively, LTP maintenance. Consistently, blockade of endogenous IL-1 or IL-6 restricts or favours hippocampal-dependent memory, effects that were confirmed in genetically manipulated mice. Since cytokines are known for their high degree of mutual crosstalk, here we studied whether a network of cytokines with known neuromodulatory actions is activated during LTP and learning. We found that, besides IL-1β and IL-6, also IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNFα are over-expressed during LTP maintenance in freely moving rats. The increased expression of these cytokines is causally related to an increase in synaptic strength since it was abrogated when LTP was interfered by blockade of NMDA-glutamate receptors. Likewise, IL-1 and IL-6 were found to be over-expressed in defined regions of the hippocampus during learning a hippocampus-dependent task. However, during learning, changes in IL-18 were restricted to the dorsal hippocampus, and no differences in TNFα and IL1-ra expression were noticed in the hippocampus. Noticeably, IL-1ra transcripts were significantly reduced in the prefrontal cortex. The relation between cytokine expression and learning was causal because such changes were not observed in animals from a pseudo-trained group that was subject to the same manipulation but could not learn the task. Taken together with previous studies, we conclude that activation of a cytokine network in the brain is a physiologic relevant phenomenon not only for LTP maintenance but also for certain types of learning.

Chronic neuropathic pain-like behavior correlates with IL-1β expression and disrupts cytokine interactions in the hippocampus.

Summary IL‐1β expression in the contralateral hippocampus coincides with neuropathic pain behavior in rats, and the correlations between hippocampal IL‐1β and IL‐1ra or IL‐6 are lost. ABSTRACT 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.

Central and peripheral cytokines mediate immune-brain connectivity.

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.

IL-1 resets glucose homeostasis at central levels

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 IL-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.