1999 Volume 46 Issue 4 Pages 487-496
Lipopolysaccharide (LPS) is known to stimulate the synthesis and secretion of various proinflammatory cytokines in both the peripheral immune cells and the brain. Yet, the relative contribution of peripheral and central cytokines to the LPS-induced activation of the hypothalamo-pituitary-adrenal axis is still poorly understood. In this study, utilizing the push-pull perfusion technique of the rat brain, we attempted to characterize in detail the temporal profiles of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α after intravenous (iv) or intraperitoneal (ip) administration of LPS in both the general circulation and the hypothalamic paraventricular nucleus (PVN), which is the primary source of corticotropin releasing hormone (CRH). Temporal changes in plasma adrenocorticotropic hormone (ACTH) and CRH levels in the PVN were also monitored. We collected blood and perfusates every 30min from 11:00 to 17:00h. At 12:00h, 1.0 or 2.5mg/kg body weight of LPS was given ia an iv or ip route, respectively. Peak ACTH response occurred 30min after iv LPS and 1.5h after ip LPS. Of the three cytokines measured in the plasma, TNF-α showed the fastest rise in synchrony with peak ACTH secretion after both iv and ip LPS. Although plasma IL-6 also showed a robust rise, its peak level occurred later than the ACTH peak. Elevation of plasma IL-1β was the smallest among the three cytokines. CRH levels in the PVN reached their peaks 1 and 2.5 h after the ACTH peak following ip and iv LPS, respectively. Irrespective of the route of LPS administration, IL-6 and TNF-α levels in the PVN showed significant rises 1-2h after the ACTH peak, but IL-1 in the PVN did not significantly change during the entire period of observation. The results of the present study suggest that circulating TNF-α may play the most important role in triggering the early, peak phase of ACTH secretion after both iv and ip LPS. Although it is possible that brain TNF-α, IL-6, and circulating IL-6, may be involved in the later, protracted phase of ACTH secretion induced by LPS, IL-1β in both the brain and peripheral circulation seems to play the smallest role in ACTH secretion. This is the first study to characterize the LPS-induced temporal changes in IL-1β, IL-6, and TNF-α in both plasma and PVN simultaneously in conscious, freely moving rats.
