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

It is well established that systemic inflammation induces a counter-regulat ory anti-inflammatory response particularly resulting in deactivation of mo nocytes/macrophages. However, recently we demonstrated a systemic anti-infl ammatory response without preceding signs of systemic inflammation in patie nts with brain injury/surgery and release of cytokines into the cerebrospin al fluid (CSF). In order to analyze the mechanisms and pathways of systemic immunodepression resulting from sterile cerebral inflammation we establish ed an animal model using continuous inh-a-cerebroventricular (i.c.v.) or in tra-hypothalamic (i.h.) infusion of rat recombinant (rr) tumor necrosis fac tor (TNF)-alpha and interleukin (n)-1 beta for 48 h. Controls received intr a-venous (i.v.) cytokine administration. Interestingly, i.c.v. and i.h. inf usion of IL-1 beta but not TNF-alpha produced distinct signs of central ner vous system (CNS) inflammation. Correspondingly, i.c.v. infusion of IL-1 be ta particularly diminished the TNF-alpha but increased the IL-10 concentrat ion in whole blood cultures after endotoxin stimulation. All parameters nor malized within 48 h after termination of the infusion. Blocking the hypotha lamic-pituitary-adrenal (HPA) axis by hypophysectomy (HPX) led to complete recovery of the diminished TNF-alpha concentration and temporarily inhibite d the IL-10 increase. Blocking the sympathetic nervous system (SNS) transmi ssion by application of the beta(2)-adrenoreceptor antagonist propranolol n ot only inhibited the increase but further downregulated the endotoxin indu ced IL-10 concentration in the media of whole blood cell cultures, whereas the TNF-alpha decrease was only partially prevented. Interestingly, HPX and propranolol also diminished the cell invasion into the CSF. In summary, ac tivation of both the HPA axis and the SNS plays an important role in system ic anti-inflammatory response resulting from cytokines in brain and cerebra l inflammation. (C) 1999 Elsevier Science B.V. All rights reserved.