ACTIONS OF CYTOKINES ON BRAIN FUNCTION

DESCRIPTION: (Applicant's Abstract): Inflammatory cytokines are present in the brain during development and consequent to a variety of neurological insults ranging from local lesions to neurodegenerative disease. The functions subserved by cytokines in the nervous system are poorly understood, however these molecules may mediate the effects of inflammatory responses on neural function, and provide a critical link between the immune and nervous systems. Initial studies from our lab and others have shown that interleukin-1 (Il-1), an important immunomodulatory cytokine, regulates expression of nerve growth factor (NGF), a neurotrophic factor critical for neuronal survival and function. The overall objective of this proposal is to define mechanisms governing the interaction between cytokines and neurotrophic factors in the brain. To identify potential cytokine-responsive cellular populations, expression of receptors for Il-1 and the related cytokine TNF will be localized in the adult and neonatal brain using in situ hybridization. To determine whether neurons and/or glial cells respond to cytokines, hippocampal cultures will be grown as separate neuronal or glial cultures and exposed to Il-1 and related inflammatory cytokines TNF and Il-6. NGF mRNA, expressed by both hippocampal neurons and astrocytes in culture, will be examined in the separate populations for responsiveness to cytokines. In addition, other members of the neurotrophin gene family, BDNF and NT-3, which are also expressed in the hippocampus, will be examined for regulation by inflammatory cytokines. Mechanisms underlying regulation of NGF by Il-1 will be characterized. The Il-1 signal transduction pathway will be examined by assessing the involvement of different second messenger systems, and by investigating the role of transcription factors such as AP-1 and NFkappaB. Thus, we propose to further define the mechanisms by which immunomodulatory cytokines influence neuronal function.