Cytokine Action on the CNS

描述：神经和免疫系统之间的适当相互作用

DESCRIPTION: Appropriate interactions between the nervous and immune systems are important for host defense. Infections, injuries and other challenges to the immune system induce the production of cytokines. Cytokine administration can elicit electrophysiological, endocrine, neurochemical and behavioral responses. Interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) activate the hypothalamo-pituitary-adrenal (HPA) axis. IL-1 and TNF-alpha increase the activity of cerebral noradrenergic neurons, all three cytokines increase brain tryptophan, and both IL-1 and IL-6 increase brain serotonin metabolism. All three cytokines have been implicated in a variety of behavioral changes, but IL-1 is clearly the most active and potent. The changes induced by cytokines resemble those associated with infection and injury making them prime candidates for messengers from the immune system to the brain. This proposal is designed to elucidate the mechanisms by which cytokines alter central nervous system function. The specific goal is to determine the significance of the effects of cytokines on brain noradrenergic and serotonergic systems, in particular their relationship to HPA activation and behavior. The noradrenergic responses to IL-1 is closely related to the HPA activation, but some evidence suggests that norepinephrine may not be necessary for HPA activation by IL-1. Prostaglandin synthesis appears to be involved in the HPA activation, and the neurochemical and behavioral responses, but may not be necessary. The significance of the changes in tryptophan and serotonin is unknown. Specific experimental objectives are: To determine the nature of the involvement of NE in the HPA activation caused by IL-1. To determine the role of cyclooxygenase (COX) involvement in the HPA, neurochemical, and behavioral responses to IL-1. To determine the mechanism(s) by which peripheral administration of IL-6 activates the HPA axis in mice. And, to determine the mechanisms of the increases in brain tryptophan and serotonin metabolism in response to IL-1beta, IL-6 and LPS.