Elsevier

Brain Research

Volume 816, Issue 2, 23 January 1999, Pages 563-571
Brain Research

Research report
Brain-IL-1β induces local inflammation but systemic anti-inflammatory response through stimulation of both hypothalamic–pituitary–adrenal axis and sympathetic nervous system

https://doi.org/10.1016/S0006-8993(98)01238-4Get rights and content

Abstract

It is well established that systemic inflammation induces a counter-regulatory anti-inflammatory response particularly resulting in deactivation of monocytes/macrophages. However, recently we demonstrated a systemic anti-inflammatory response without preceding signs of systemic inflammation in patients with brain injury/surgery and release of cytokines into the cerebrospinal fluid (CSF). In order to analyze the mechanisms and pathways of systemic immunodepression resulting from sterile cerebral inflammation we established an animal model using continuous intra-cerebroventricular (i.c.v.) or intra-hypothalamic (i.h.) infusion of rat recombinant (rr) tumor necrosis factor (TNF)-α and interleukin (IL)-1β for 48 h. Controls received intra-venous (i.v.) cytokine administration. Interestingly, i.c.v. and i.h. infusion of IL-1β but not TNF-α produced distinct signs of central nervous system (CNS) inflammation. Correspondingly, i.c.v. infusion of IL-1β particularly diminished the TNF-α but increased the IL-10 concentration in whole blood cultures after endotoxin stimulation. All parameters normalized within 48 h after termination of the infusion. Blocking the hypothalamic–pituitary–adrenal (HPA) axis by hypophysectomy (HPX) led to complete recovery of the diminished TNF-α concentration and temporarily inhibited the IL-10 increase. Blocking the sympathetic nervous system (SNS) transmission by application of the β2-adrenoreceptor antagonist propranolol not only inhibited the increase but further downregulated the endotoxin induced IL-10 concentration in the media of whole blood cell cultures, whereas the TNF-α decrease was only partially prevented. Interestingly, HPX and propranolol also diminished the cell invasion into the CSF. In summary, activation of both the HPA axis and the SNS plays an important role in systemic anti-inflammatory response resulting from cytokines in brain and cerebral inflammation.

Introduction

Local infection or sterile trauma induce a local inflammatory response. The release of pro-inflammatory cytokines (e.g. TNF-α, IL-1β) activates an inflammatory cascade improving wound healing and anti-microbial defense. Monocytes/macrophages are important players in this scenario. However, overwhelming response can result in systemic inflammation and septic shock. In order to control the potentially harmful inflammatory response, the immune system can release several anti-inflammatory mediators like IL-10, IL-1 receptor antagonist (ra) and soluble TNF-receptors. TNF-α, IL-1β and prostaglandins by themselves are powerful inducers of the compensatory anti-inflammatory response. However, there is evidence that in addition to the auto-regulatory pathways of the immune cells the delicate balance between pro- and anti-inflammatory response is controlled by the CNS.

This is most evident in the release of different mediators by pituitary and adrenal glands that follows over-spill of IL-1β, TNF-α and IL-6 into the circulation 4, 10, 18, 26, 32, 37. Moreover, pro-inflammatory cytokines (e.g., IL-1β) can enhance sympathetic nerve activity 15, 20, 34. Remarkably, in vitro studies demonstrated that catecholamines are able to upregulate the endotoxin induced release of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells whereas the TNF-α production was down-regulated 7, 22, 27, 35. Consequently, an activation of CNS pathways by mediators of the immune system may induce a brain-mediated anti-inflammatory response in order to control systemic inflammation 16, 21.

However, the question is, what happens if the immuno-inhibitory CNS pathways are activated without systemic inflammation? Recently, we demonstrated that postoperative release of pro-inflammatory cytokines into the CSF without any signs of systemic inflammation was associated with immunodepression and an increased risk of infections in neurosurgical patients 1, 2, 39, 40. Immunodepression was reflected by the down-regulation of monocytic HLA-DR expression and ex vivo TNF-α production. In parallel, elevated plasma IL-10 levels were seen. Similar findings were observed in patients suffering from brain injury [39]. That means that cytokines in the brain can trigger a systemic anti-inflammatory condition without preceding systemic inflammation. Persistence of this phenomenon increases the risk for infectious complications.

In order to further complete the knowledge about local inflammation in the CNS and the consequences for the systemic immune response, an animal model was established using continuous i.c.v. or i.h. (hypothalamus is the hypothesized site of action for brain-IL-1β) infusion of rat recombinant (rr)IL-1β and rrTNF-α, both most important pro-inflammatory cytokines, for two days. The aim of the study was to characterize local and systemic immune consequences resulting from cytokines in the brain. Therefore, we measured cell numbers in the CSF and monitored changes in the functional state of inflammatory immune cells (particularly monocytes) by measuring the concentration of TNF-α and IL-10 in the supernatants of whole blood cell cultures as well as spleen cell cultures after endotoxin stimulation. In order to evaluate the importance of the HPA axis and the SNS for the immune effects additional experiments were performed with hypophysectomized rats and blocking β2-adrenoreceptors with propranolol. To analyze the recovery of the immunological changes, investigations were extended to 48 h after termination of the IL-1β infusion in one group.

Section snippets

Animals

Approval for the study was achieved from the Animal Protection Board of the Senat of Berlin. A total of 120 male Sprague–Dawley rats (Harlan Winkelmann, Borchen, Germany) weighing 250–350 g at the time of surgery were used. The animals were divided into 12 groups of 10 rats each. Three different solutions: vehicle (4% HSA dissolved in physiological saline), (DRK-Blutspendedienst, Springe, Germany), rrIL-1β (R&D systems, Minneapolis, USA) and rrTNF-α (Laboserv, Staufenberg, Germany) were

Histological verification of the cannula position

In all animals with implanted brain cannulas the correct position of the cannula was verified histologically. Only data from animals with correct cannula placement and without injury to the surrounding brain (at least 9 from 10 animals in each group) were evaluated.

Alterations in body weight and behavior of the animals during cytokine infusion

The i.c.v. and i.h. infusion of IL-1β at the dose of 10 ng/h produced signs of physical discomfort in all animals including piloerection and decreased physical activity during the infusion time of 48 h. The infused dose of 10 ng/h

Discussion

In response to an inciting event such as infection, hemorrhage, or trauma the body unleashes an inflammatory reaction that is capable of amplifying itself indefinitely. However, little is known how the body might down-regulate the inflammatory cascade. Evidence is accumulating that in response to the original inciting event (the inflammatory response) the body also mounts an anti-inflammatory response [29]. Several studies demonstrated the induction of anti-inflammatory factors by

Conclusion

Our results demonstrate that i.c.v. and i.h. infusion of IL-1β at the dose of 10 ng/h for 48 h cause a severe CNS inflammation whereas TNF-α infusion at the same dose is less effective. Correspondingly, an acute systemic immunodepression with decreased endotoxin induced concentration of pro-inflammatory cytokines (TNF-α) and increased concentration of anti-inflammatory cytokines (IL-10) in the supernatants of whole blood cell cultures was observed. These data suggest that pro-inflammatory

Acknowledgements

This work was supported by a grant from the Deutsche Forschungsgemeinschaft, SFB 507/C5.

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