Temporal profiles of interleukin-1 beta, interleukin-6, and tumor necrosisfactor-alpha in the plasma and hypothalamic paraventricular nucleus after intravenous or intraperitoneal administration of lipopolysaccharide in the rat: Estimation by push-pull perfusion

Lipopolysaccharide (LPS) is known to stimulate the synthesis and secretion of various proinflammatory cytokines in both the peripheral immune cells an d the brain. Yet, the relative contribution of peripheral and central cytok ines to the LPS-induced activation of the hypothalamo-pituitary-adrenal axi s is still poorly understood. In this study, utilizing the push-pull perfus ion technique of the rat brain, we attempted to characterize in detail the temporal profiles of interleukin (IL)-1 beta, IL-6, and tumor necrosis fact or (TNF)-alpha after intravenous (iv) or intraperitoneal (ip) administratio n of LPS in both the general circulation and the hypothalamic paraventricul ar nucleus (PVN), which is the primary source of corticotropin releasing ho rmone (CRH). Temporal changes in plasma adrenocorticotropic hormone (ACTH) and CRH levels in the PVN were also monitored. We collected blood and perfu sates every 30 min from 11:00 to 17:00 h. At 12:00 h, 1.0 or 2.5 mg/kg body weight of LPS was given via an iv or ip route, respectively. Peak ACTH res ponse occurred 30 min after iv LPS and 1.5 h after ip LPS. Of the three cyt okines measured in the plasma, TNF-a showed the fastest rise in synchrony w ith 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. El evation of plasma IL-1 beta was the smallest among the three cytokines. CRH levels in the PVN reached their peaks 1 and 2.5 h after the ACTH peak foll owing ip and iv LPS, respectively. Irrespective of the route of LPS adminis tration, IL-6 and TNF-alpha levels in the PVN showed significant rises 1-2 h after the ACTH peak, but IL-1 beta in the PVN did not significantly chang e during the entire period of observation. The results of the present study suggest that circulating TNF-alpha may play the most important role in tri ggering the early, peak phase of ACTH secretion after both iv and ip LPS. A lthough it is possible that brain TNF-alpha, IL-6, and circulating IL-6, ma y be involved in the later, protracted phase of ACTH secretion induced by L PS, IL-1 beta in both the brain and peripheral circulation seems to play th e smallest role in ACTH secretion. This is the first study to characterize the LPS-induced temporal changes in IL-1 beta, IL-6, and TNF-alpha in both plasma and PVN simultaneously in conscious, freely moving rats.