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ABSTRACT
Activated cells of the monocyte—macrophage lineage produce two forms of the inflammatory cytokine interleukin-1 (IL-1), IL-1α and IL-1β, of which IL-1β is the predominant secreted form and has a wide range of modulatory effects on the endocrine system. Immunoassays of human IL-1β have been described, but are not suitable for measurement of rat and mouse IL-1β because of limited cross-reactivity. Polyclonal sheep anti-rat or sheep anti-mouse IL-1β antisera were used to develop sensitive and specific immunoradiometric assays for rat and mouse IL-1β. Secretion of IL-1β from endotoxin-activated monocytes or macrophages was measured in vitro or in vivo in both species. In vitro, rat monocytes and mouse macrophages produced IL-1β in response to endotoxin, with a relatively small proportion of total IL-1β being secreted. In vivo, endotoxin stimulated an increase in plasma IL-1β in both animals. The development of these assays will facilitate studies of the role of endogenous IL-1β in animal endocrine models.
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ABSTRACT
Regulation of a number of aspects of the acute-phase response, including induction of fever and activation of the hypothalamo-pituitary-adrenal axis, occurs within the hypothalamus. The acute-phase response appears to be co-ordinated by the inflammatory cytokine interleukin-1 (IL-1). A number of studies using hybridization techniques to measure IL-1 gene expression and immunocyto-chemistry to localize immunoactive IL-1 have established the concept that the central nervous system, and in particular the hypothalamus, is a site of IL-1 production, and that levels increase in response to inflammatory stimuli. In this report we present data on the levels of IL-1β produced in the rat hypothalamus using quantitative immunoassay techniques. Bacterial endotoxin, administered to rats in vivo, evoked increases in hypothalamic IL-1β levels which were significant within 1 h, and reached maximum levels at 5–10 h. The response to endotoxin was dose-related, and levels reached in hypothalamic extracts corresponded to intra-hypothalamic levels of the order of 20 ng/ml. During short-term in-vitro culture of rat hypothalami, endotoxin stimulated a dose-related increase in both the synthesis and the secretion of IL-1β, which reached similar levels to those seen after in-vivo stimulation. Hypothalami obtained from animals stimulated with endotoxin in vivo did not, however, show any evidence of persistent stimulation of IL-1β production when subsequently cultured in vitro.
These data support the concept that production of hypothalamic IL-1 is an essential step in regulating the activity of the hypothalamus during the acute-phase response, and provide for the first time quantitative data on the magnitude, dose—response relationships and time-courses of rat hypothalamic IL-1β production in vivo and in vitro.
