Bacterial endotoxins such as Escherichia coli lipopolysaccharide (LPS) bind to specific Toll-like receptors in fixed and circulating immunocompetent cells and activate the sympathetic and pituitary-adrenal system through similar receptors in cells that form the blood-brain interface. The latter, in turn, lead to the formation, within the brain, of proinflammatory cytokines including interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), and one or more antinflammatory cytokines including tumor growth factor beta (TGF-beta), and IL-10. Although the full panoply of central cytokines can be activated after systemic exposure, direct introduction of IL-1beta into the brain exerts a unique pattern of peripheral immune responses attributable to the special properties of reactive cells within the brain and to the "reservoir" function of the cerebrospinal fluid compartment. De Simoni et al. were the first to show that the intracerebroventricular (icv) injection of IL-1beta in rats induced a dramatic increase in the concentration of circulating IL-6 that was much greater and more prolonged than that induced by intravenous bolus injection of the same dose of cytokine. The work reported in this paper shows that the "De Simoni paradox" is mainly due to the prolonged release of the injected IL-1beta from brain to blood: a large proportion is not degraded (86%), transport out is both active and passive, and the initial exposure to IL-1beta sensitizes peripheral responses to the continuing exposure to the cytokine. Although IL-6, TNF-alpha and LPS are passively transferred from brain to blood (as shown by radioiodine-labeled tracer studies) peripheral cytokine responses to central injection differ from responses to IL-1beta. Peripheral responses to central TNF-alpha are similar to those after peripheral administration because TNF-alpha has no peripheral sensitizing effect. Peripheral response to central LPS exposure is much less than that which occurs when an amount identical with that transferred from brain to blood is administered peripherally. This is due to the fact that intracerebral injection of LPS suppresses response to peripherally administered endotoxin. Since the effect can still be demonstrated in adrenalectomized animals maintained on a constant dose of corticosterone, the brain has the capacity by as yet undefined mechanisms to suppress peripheral inflammatory responses.