Hugo O. Besedovsky

Immunoregulation mediated by the sympathetic nervous system.

Abstract A postulated immunoregulatory role for the autonomous nervous system was explored utilizing several in vivo and in vitro approaches. Local surgical denervation of the spleen in rats and general chemical sympathectomy by 6-hydroxydopamine combined with adrenalectomy yielded a similar removal of restraint expressed as enhancement in the number of PFC in response to immunization. Noradrenaline and the synthetic α-agonist clonidine which are, respectively, natural and artificial effector molecules of the sympathetic nervous system each strongly suppressed the in vitro induced immune response of murine spleen cells to SRBC. Further, radiometric-enzymatic assay of noradrenaline in the splenic pulp revealed a decrease in the content of this neurotransmitter just preceding the exponential phase of the immune response to SRBC (Days 3 and 4) in this site. Taken together, these findings point to a dynamic immunoregulatory relationship between the immune and sympathetic nervous system.

Cytokines as modulators of the hypothalamus-pituitary-adrenal axis

The hypothalamus-pituitary-adrenal (HPA) axis is stimulated during the course of certain immune, inflammatory and neoplastic processes. IL-1 is an important immunologically derived cytokine mediating the stimulation of this axis, although not the only one. We have compared the relative potencies of the cytokines IL-1, IL-6 and tumor necrosis factor (TNF), which share several biological actions, for stimulating ACTH and corticosterone output in freely-moving rats. Although all three cytokines can stimulate the HPA axis, IL-1 was the most potent. This effect of IL-1 was also present during the neonatal period, when the response of the HPA axis to acute stress is reduced in rodents. The results support the existence of an immune-HPA axis circuit. The biological and clinical relevance of this circuit is discussed.

Interleukin-6: a cytokine to forget

It is known that proinflammatory cytokines such as interleukin‐6 (IL‐6) are expressed in the central nervous system (CNS) during disease conditions and affect several brain functions including memory and learning. In contrast to these effects observed during pathological conditions, here we describe a physiological function of IL‐6 in the “healthy” brain in synaptic plasticity and memory consolidation. During long‐term potentiation (LTP) in vitro and in freely moving rats, IL‐6 gene expression in the hippocampus was substantially increased. This increase was long lasting, specific to potentiation, and was prevented by inhibition of N‐methyl‐D‐aspartate receptors with (±)‐2‐amino‐5‐phosphonopentanoic acid (AP‐5). Blockade of endogenous IL‐6 by application of a neutralizing anti‐IL6 antibody 90 min after tetanus caused a remarkable prolongation of LTP. Consistently, blockade of endogenous IL‐6, 90 min after hippocampus‐dependent spatial alternation learning resulted in a significant improvement of long‐term memory. In view of the suggested role of LTP in memory formation, these data implicate IL‐6 in the mechanisms controlling the kinetics and amount of information storage.

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.

The cytokine-HPA axis feed-back circuit

Zusammenfassung Wegen ihrer anti-inflammatorischen Effekte und ihrer Potenz, die Synthese der meisten Zytokine und die Balance Th1/Th2 zu beeinflussen, tragen die endogenen Glukokortikoide zur basalen Regulation der Immunzellen bei. Immunologische Prozesse verursachen die Produktion von Zytokinen, wie IL-1, IL-2, IL-6, IL-11, IL-12, TNF-α, INF-γ, welche ihrerseits die HPA Achse stimulieren können. Der dadurch vermittelte Anstieg von Glukokortikoiden wirkt entweder direkt oder über die Beeinflussung der Produktion von Zytokinen auf immunologische Zellen, was die Existenz eines zytokinvermittelten immunregulatorischen Regelkreises mit der HPA Achse nahelegt. Es gilt als gesichert, dass dieser Regelkreis eine bedeutsame Rolle spielt bei der Kontrolle einer überschießenden Immunantwort und der Unterdrückung der Expansion von Immunzellen mit fehlender oder nur geringer Affinität zu Antigenen, welche die spezifische Immunantwort auslösen.Summary Due to their anti-inflammatory effects and their capacity to affect the synthesis of most cytokines and the Th1/Th2 balance, endogenous glucocorticoids contribute to control the basal operation of immune cells. Immune processes result in the production of cytokines, such as IL-1, IL-2, IL-6, IL-11, IL-12, TNF-α, and INF-γ, which can activate the HPA axis. In turn, the resulting increase in glucocorticoid blood levels can affect immune cell activity directly or by controlling the production of cytokines, suggesting the existence of an immunoregulatory cytokine-HPA axis circuit. There is evidence that this circuit plays a relevant role in controlling excessive inflammatory reactions and the non-specific expansion of immune cells with no or low affinity for the antigen that triggers an immune response.

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.