CYTOKINE STIMULATION INCREASES INTRACELLULAR CALCIUM AND ALTERS THE RESPONSE TO QUISQUALATE IN CULTURED CORTICAL ASTROCYTES

Cytokine levels are elevated in the central nervous system (CNS) in a variety of disorders and may contribute to abnormalities in CNS functi on associated with the disorders. To begin to understand the mechanism s through which elevated cytokines affect CNS cells, we have examined the effects of cytokines on astrocyte physiology within minutes of app lication as well as 24 h later. Both standard cultured cortical astroc ytes and those induced to further differentiate by pre-treatment with forskolin were examined. Such treated astrocytes may more closely rese mble those in brains exhibiting elevated cytokine levels. The cytokine focused upon was interleukin-1-beta (Il-1beta). Gamma-interferon (gam ma-IFN) and tumor necrosis factor-alpha (TNF-alpha) were also examined in some studies. Changes in calcium levels produced by acute applicat ion of these cytokines were measured. The most pronounced effect was a n immediate calcium elevation in response to Il-1beta in the forskolin pre-treated astrocytes. Longer term treatment with IL-1beta in forsko lin pre-treated astrocytes enhanced the calcium response to quisqualat e stimulation, a glutamate neurotransmitter receptor agonist. These re sults suggest that situations that cause chronic changes in cytokine l evels and involve astrocytic differentiation, such as chronic CNS infe ction or Alzheimer's disease, could change astrocytic responses to nor mal stimuli. Such changes may result in altered astrocytic support of neurons and therefore cause changes in CNS function.