title: Taurine blunts LPS-induced increases in intracellular calcium and TNF-alpha production by Kupffer cells.
abstract: 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 microM) and was prevented when chloride was removed from the extracellular media. Moreover, taurine increased 36Cl- uptake by Kupffer cells in a dose-dependent manner (EC50, 0.2 mM). Furthermore, strychnine (1 microM) reversed the effect of taurine on 36Cl- 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.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, 27599-7365, USA.
authors.forename: V
authors.initials: V
authors.lastname: Seabra
authors.forename: R F
authors.initials: RF
authors.lastname: Stachlewitz
authors.forename: R G
authors.initials: RG
authors.lastname: Thurman
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013331:Strychnine / Q000494:pharmacology; D013654:Taurine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013654:Taurine; D013331:Strychnine; D002118:Calcium