Different roles of brain interleukin 1 in the adrenocorticotropin response to central versus peripheral administration of lipopolysaccharide in the rat

Although it is well established that peripheral administration of endotoxin activates the hypothalamic-pituitary-adrenal (HPA) axis, information is very limited regarding whether central administration of endotoxin can similarly stimulate the endocrine axis. Moreover, it is also unknown whether a difference exists in the mode of involvement of brain-derived cytokines in determining the HPA response to peripheral vs central administration of endotoxin. In the present study, the authors attempted to gain more knowledge on these issues focusing on interleukin (IL) 1 in the brain, one of key pro-inflammatory cytokines mediating the immuno-endocrine network. In male rats, both intravenous (i.v., 100 micrograms/kg body weight) and intracerebroventricular [i.c.v. (the 3rd ventricle), 10 micrograms] injections of Escherichia coli lipopolysaccharide (LPS) caused a significant elevation of adrenocorticotropin (ACTH) levels in plasma, even though peaked ACTH responses occurred earlier after the i.v. (60 min post-injection) than the i.c.v. (120 min post-injection) LPS. Although the ACTH response to i.c.v. LPS was significantly suppressed by a prior (5 min) i.c.v. administration of IL-1 receptor antagonist (IL-1Ra, 1 microgram), the hormonal response to i.v. LPS was not. That this dose of IL-1Ra was not biologically a small dose was indicated by another experiment that the same dose of i.c.v. IL-1Ra was able to significantly suppress the ACTH response to an i.c.v. injection of recombinant human IL-1 beta (50 ng). These results suggest that i.c.v. LPS, as i.v. LPS, can stimulate ACTH secretion in the rat, and this hormonal response may, at least in part, be mediated by brain-derived IL-1. Although there is one previous study reporting an important role of central IL-1 in mediating the HPA response to systemic LPS treatment, our present data suggest that such a mechanism may not operate before and during an early, peak phase of ACTH secretion after i.v. LPS.