The Interleukin-1 family of proteins in the brain and adrenal gland : regulation in response to bacterial LPS

Sammanfattning: Interleukin-1 (IL-1) is mediating diverse physiological conditions as inflammatory response, fever and sickness behaviour but also, via activation of the hypothalamus-pituitary-adrenal (HPA)-axis, the release of the anti-inflammatory adrenocorticoids. The neuroendocrine system as well as the central nervous system (CNS) is involved in the regulation of these conditions in the body. In this thesis the overall questions have been where and how the regulation of IL-1 is excerted during peripheral gram negative (-) bacterial infection, mimicked by injection of the molecule lipopolysaccharide (LPS), isolated from E.Coli bacteria.We have demonstrated a cell specific distribution of the interleukin-1 (IL-1) family proteins in the neuroendocrine rat adrenal gland. IL-1? was found to be restricted to the noradrenergic cells whereas IL-1? and IL-1 receptor antagonist (IL-1ra) were detected in both noradrenergic and adrenergic cells of the adrenal medulla. A role for IL-1?during cell differentiation was indicated, since the IL-1 content was increased by nerve growth factor (NGF) in PC12 cells, a cell line derived from adrenal noradrenergic chromaffin cells. Bioactive IL-1?is produced after cleavage of the inactive proIL-1?precursor protein by the IL-1?converting enzyme (ICE). Several isoforms of ICE mRNA were detected in the rat adrenal gland and the expression of these isoforms was changed after LPS injection. The presence of a dynamic IL-1 system in the chromaffin cells of the adrenal gland indicates a role for IL-1 in the adrenal during sickness as well as in health.The importance of IL-1 in the brain is still not fully understood. In normal rats and mice peripheral LPS administration induces IL-1 expression in the CNS. In the rat brain we could detect a region specific regulation of proIL-1?processing by ICE after LPS injection. In an attempt to further evaluate the role of central IL-1 in the acute phase response to LPS, a transgenic mouse strain with constitutive brain-specific expression of the secreted form of the IL-1ra (sIL-1ra) was developed. However, over expression of sIL-1ra, and consequently blockage of IL-1 receptors in the CNS, did not affect the LPS-induced fever or the increased plasma concentrations of IL-1?or IL-6. These results indicate that regulation of the CNS pool of IL-1 is not mediating peripheral LPS-induced fever.