A study on the regulatory mechanism of the hypothalamo-pituitary-adrenal axis

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1.It is known that systemic administration of lipopolysaccharide (LPS) stimulates the synthesis and secretion of various proinflammatory cytokines in both the general circulation and the brain. Thus, the relative contribution of peripheral and central cytokines to the activation of the corticotropin-releasing hormone (CRH) -adrenocorticotropin (ACTH) system is still poorly understood. In the present research project, this principal investigator attempted to examine this unresolved issue in more details. The results I obtained suggested that tumor necrosis factor (TNF) -alpha in the general circulation may play the most important role in triggering the early, peak phase of ACTH secretion after systemic LPS treatment in the rat.2.It has been repeatedly reported that indomethacin suppress the ACTH response to interleukin (IL) -1beta in the rat. Although this finding was construed as suggesting a stimulatory role of prostaglandins in mediating the hormonal response, a group of investigators have reported that this may not be the case. In the present study, this principal investigator attempted to clarify this issue, and found that the suppression by indomethacin of the IL-1beta-induced ACTH response is mediated by indomethacin's inherent pharmacological activity, i.e.the suppression of prostaglandin production.3.Utilizing IL-1 receptor antagonist which blocks the biological activity of IL-1, this proncipal investigator examined the involvement of brain IL-1 in mediating the ACTH response to intravenous or intracerebroventricular administration of LPS in the rat. Implications deriving from this study were that IL-1 in the brain may play an important role in mediating the ACTH secretion after intracerebroventricular, but not intravenous, administration of LPS in the rat.