Taurine blunts LPS-induced increases in intracellular calcium and TNF-α production by Kupffer cells

Activation of Kupffer cells by lipopolysaccharide (LPS) plays a pivotal role in the onset of pathophysiological events that occur during endotoxemia and intracellular calcium ([Ca2+](i)) is involved in LPS-stimulated cytokine production. Recently, it was shown that Kupffer cells contain a glycine gated chloride channel. Because taurine, a ubiquitous sulfur-containing beta-amino acid, acts similarly to glycine in neurons by causing hyperpolarization, it was hypothesized that taurine would 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-induced changes in [Ca2+](i) were monitored fluorometrically in single cells, whereas levels of tumor necrosis factor alpha (TNF-alpha) released by Kupffer cells after exposure to LPS were measured by enzyme-linked 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 chloride was removed from the extracellular media. Moreover, taurine increased Cl-36(-) uptake by Kupffer cells in a dose-dependent manner (EC50, 0.2 mM), Furthermore, strychnine (1 mu M) reversed the effect of taurine on Cl-36(-) uptake. These results indicate that taurine activates a glycine-gated chloride channel in Kupffer cells causing chloride influx. In addition, LPS-induced TNF-alpha production was reduced by more than 40% by taurine, an effect that was also reversed by strychnine, In conclusion, taurine blocks the increase in [Ca2+](i) due to LPS and significantly reduces TNF-alpha production by mechanisms involving chloride influx into the Kupffer cell.