PROTEIN-TYROSINE KINASE INHIBITORS DECREASE LIPOPOLYSACCHARIDE-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION IN MIXED GLIA, MICROGLIA-ENRICHED OR ASTROCYTE-ENRICHED CULTURES

Proinflammatory cytokines, tumor necrosis factor-alpha (TNF alpha), in terleukin-1 (IL-1), and interleukin-6 (IL-6), produced by glial cells have been implicated in the neuropathogenesis of various diseases. How ever, the signal transduction pathway(s) for the production of these c ytokines in glial cells are not well understood. This study examined t he effects of two potent protein tyrosine kinase inhibitors, genistein and tyrphostin A25, on lipopolysaccharide (LPS)-induced production of TNF alpha, IL-1 alpha, and IL-6 in mouse primary mixed glia, microgli a- or astrocyte-enriched cultures. LPS dose-dependently increased the production of TNF alpha, IL-1 alpha, and IL-6 from the mixed glia cult ures. Genistein or tyrphostin A25 significantly inhibited the LPS-indu ced production of these cytokines. The LPS-induced TNF alpha, IL-1 alp ha, and IL-6 production in microglia- or astrocyte-enriched cultures w ere also inhibited by tyrphostin A25. These results demonstrate that p rotein tyrosine kinases are involved in the signaling events of the LP S-induced production of TNF alpha, IL-1 alpha, or IL-6 in microglia or astrocytes, which may provide insights into therapeutic interventions in the pathway for cytokine production in the brain. Published by Els evier Science Ltd.