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N Yu, D Maciejewski-Lenoir, FE Bloom and PJ Magistretti
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Cytokines can be produced within the nervous system by various cell types, including astrocytes, which secrete them in response to pathological processes such as viral infections. Astrocytes are known to play an important role in the homeostasis of the nervous system, in particular, by contributing to the regulation of local energy metabolism. We report that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) markedly stimulate glucose uptake and phosphorylation in primary cultures of neonatal murine astrocytes, as determined with [3H]-2-deoxyglucose ([3H]2DG). This effect is both concentration dependent, with observed EC50 values of 8 ng/ml for TNF- alpha and 30 pg/ml for IL-1 alpha, and time dependent, with a maximal response observed 24 hr after cytokine application. The effects of TNF- alpha and IL-1 alpha on glucose uptake and phosphorylation appear to be mediated by the phospholipase A2 signal transduction pathway. Evidence in support of this includes (i) inhibition by mepacrine, a phospholipase A2 inhibitor, of [3H]2DG uptake evoked by TNF-alpha and IL-1 alpha, and (ii) stimulation of [3H]arachidonic acid release by TNF- alpha and IL-1 alpha. Protein kinase C activation does not appear to be involved as the specific protein kinase C inhibitor Ro 31-7549 does not abolish TNF-alpha- or IL-1 alpha-induced increase in [3H]2DG uptake and phosphorylation. The additional glucose imported by astrocytes on exposure to TNF-alpha and IL-1 alpha is neither stored as glycogen nor released as glycolytically derived lactate, suggesting that it is processed through the tricarboxylic acid cycle or pentose phosphate pathway. These results demonstrate that TNF-alpha and IL-1 alpha can fundamentally perturb the energy metabolism of astrocytes, possibly impairing their ability to provide adequate energy substrates for neurons.
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