TAURINE BLUNTS LPS-INDUCED INCREASES IN INTRACELLULAR CALCIUM AND TNF-ALPHA PRODUCTION BY KUPFFER CELLS

Activation of Kupffer cells by lipopolysaccharide (LPS) plays a pivota l role in the onset of pathophysiological events that occur during end otoxemia and intracellular calcium ([Ca2+](i)) is involved in LPS-stim ulated cytokine production. Recently, it was shown that Kupffer cells contain a glycine gated chloride channel. Because taurine, a ubiquitou s sulfur-containing beta-amino acid, acts similarly to glycine in neur ons by causing hyperpolarization, it was hypothesized that taurine wou ld act via a similar mechanism, blunting the LPS-induced increase in [ Ca2+](i) in Kupffer cells. To test this hypothesis, Kupffer cells were isolated from female Sprague-Dawley rats and cultured for 24 h, LPS-i nduced changes in [Ca2+](i) were monitored fluorometrically in single cells, whereas levels of tumor necrosis factor alpha (TNF-alpha) relea sed by Kupffer cells after exposure to LPS were measured by enzyme-lin ked immunosorbent assay. Taurine significantly blunted the LPS-induced increase in [Ca2+](i) in a dose-dependent manner (IC50, 0.1 mM), This effect was reversed by strychnine (1 mu M) and was prevented when chl oride was removed from the extracellular media. Moreover, taurine incr eased Cl-36(-) uptake by Kupffer cells in a dose-dependent manner (EC5 0, 0.2 mM), Furthermore, strychnine (1 mu M) reversed the effect of ta urine on Cl-36(-) uptake. These results indicate that taurine activate s a glycine-gated chloride channel in Kupffer cells causing chloride i nflux. In addition, LPS-induced TNF-alpha production was reduced by mo re than 40% by taurine, an effect that was also reversed by strychnine , In conclusion, taurine blocks the increase in [Ca2+](i) due to LPS a nd significantly reduces TNF-alpha production by mechanisms involving chloride influx into the Kupffer cell.