Tumor necrosis factor-α and interleukin-1α enhance glucose utilization by astrocytes: Involvement of phospholipase A₂

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-α (TNF-α) and interleukin-1α (IL-1α) 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-α and 30 pg/ml for IL-1α, and time dependent, with a maximal response observed 24 hr after cytokine application. The effects of TNF-α and IL-1α 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-α and IL-1α, and (ii) stimulation of [³H]arachidonic acid release by TNF-α and IL-1α. Protein kinase C activation does not appear to be involved as the specific protein kinase C inhibitor Ro 31-7549 does not abolish TNF-α- or IL-1α-induced increase in [³H]2DG uptake and phosphorylation. The additional glucose imported by astrocytes on exposure to TNF-α and IL-1α 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-α and IL-1α can fundamentally perturb the energy metabolism of astrocytes, possibly impairing their ability to provide adequate energy substrates for neurons.