Taurine chloramine inhibits inducible nitric oxide synthase and TNF-alpha gene expression in activated alveolar macrophages: Decreased NF-kappa B activation and I kappa B kinase activity

Taurine prevents tissue damage in a variety of models that involve inflamma tion, including oxidant-induced lung damage. The mechanism of protection is uncertain, but is postulated to involve the actions of taurine chloramine (Tau-Cl) derived via halide-dependent myeloperoxidase associated with neutr ophils. Understanding the influence of Tau-Cl on the production of inflamma tory mediators by alveolar macrophages provides an opportunity for determin ing the mechanism of Tau-CI action. The effects of Tau-Cl were evaluated on the production of NO and TNF-alpha in NR8383, a cloned cell line derived f rom rat alveolar macrophages (RAM), and in primary cultures of RAM. Product ion of NO and TNF-alpha, and expression of inducible NO synthase was inhibi ted by Tau-Cl in activated NR8383 cells as well as in RAM. Temporal (2, 4, 8, 24 h) expression of inducible NO synthase and TNF-a mRNAs was reduced by Tau-Cl in NR8383 cells. Tau-Cl depressed NF-kappaB migration into the nucl eus of activated NR8383 cells and caused a more sustained presence of I kap paB in the cytoplasm. Stabilization of cytoplasmic I kappaB-alpha in Tau-Cl -treated cells resulted from decreased phosphorylation of I kappaB-alpha se rine-32 and a lower activity of I kappaB kinase (IKK). Additional experimen ts demonstrated that Tau-Cl does not directly inhibit IKK activity. These r esults suggest that Tau-Cl exerts its effects at some level upstream of IKK in the signaling pathway and inhibits production of inflammatory mediators through a mechanism that, at least in part, involves inhibition of NF-kapp aB activation.