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

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 β 2-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.