Cytokines interact with the nervous system in numerous ways. These molecules are expressed within the central nervous system (CNS) 1 and play an important role in neuronal cell death and survival. In addition, peripheral cytokines released from immune cells during inflammation can stimulate a variety of physiological, neuroendocrine, and behavioral responses of the CNS, including fever, sleep, hypothalamic-pituitary-adrenal (HPA) axis activation, sickness, and other behaviors. The nervous system, in turn, regulates the immune system via several routes, systemic and local, including neuroendocrine pathways and the autonomic and peripheral nervous systems (Fig. 1). To date, virtually all known cytokines or their receptors have been sought (and found) in many CNS cells, including neurons (1–7). Many experimental approaches have been used to define the extent to which cytokines and their receptors are expressed in nervous system tissues and the extent to which these tissues respond to cytokines. These include in situ hybridization and Northern blot analysis for mRNA expression; radioimmunoassay and ELISA for peptide content; autoradiographic localization of receptors by radiolabeled cytokine binding in brain slices; immunohistochemistry to define cytokine pathways in the nervous system; neuropeptide secretion by brain explants, primary cell cultures, or cell lines exposed to cytokines and cytokine production by brain explants, primary cell cultures, or cell lines exposed to neuropeptides (7). Table I shows the extent to which these molecules have been identified in neurons, astrocytes, oligodendrocytes, and microglia by these approaches.

Cytokines can be expressed under resting physiological conditions in these resident CNS cells, but are also induced during injury and development. In addition, under pathological conditions, cytokines can be expressed in infiltrating macrophages in the brain. Northern blot analysis, RT-PCR, and in situ hybridization for cytokine mRNAs have been used to identify cytokine overexpression in CNS tissue in various dis-