Sickness behaviour and acute and chronic inflammation in the central nervous system

It was demonstrated here that acute sickness behaviour (febrile response) induced by the bolus injection of IL-1β into the rat CNS could be attenuated by a concurrent acute ischaemic lesion. The presence of IL-1β significantly attenuated the neuronal loss that resulted from focal ischaemia in a manner similar to that described in neuronal ischaemic preconditioning (IP/IT). This may suggest that mechanisms of neuronal IP/IT that are typically induced in the CNS by acute sub-threshold ischaemic events, and that give rise to endogenous neuroprotein, can also be induced by IL-1β and can attenuate any associated sickness behaviour. Chronic expression of IK-1β in the rat CNS resulted in a long-lived local inflammatory response, characterised by leucocyte recruitment and focal neuronal loss, but only transient sickness behaviour (febrile response), suggesting that within the brain there are adaptive mechanisms that confer a state of "metabolic tolerance" to the chronic expression of proinflammatory cytokines. The onset of metabolic tolerance was associated with a marked attenuation in the expression of pyrogenic cytokines at central sites of thermoregulation (hypothalamus), but could be overridden by a secondary peripheral immune challenge (LPS), giving rise to exaggerated febrile responses; this was also associated with an increase in the expression of proinflammatory cytokines at the primary site of inflammation within the CNS. This is likely to be of great clinical significance, particularly in the treatment of common peripheral infections in individuals with pre-existing inflammatory disease of the CNS, or in individuals where the immune system is chronically activated, such as the healthy aged. The results of these studies raise the important issue that treatments designed to prolong the life of individuals with terminal chronic neurodegenerative disease of the CNS may not necessarily alleviate the associated symptoms, and may not protect against the underlying pathology.