Taurine chloramine inhibits inducible nitric oxide synthase and TNF-alpha gene expression in activated alveolar macrophages: decreased NF-kappaB activation and IkappaB kinase activity.
Taurine prevents tissue damage in a variety of models that involve inflammation, 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 neutrophils. Understanding the influence of Tau-Cl on the production of inflammatory mediators by alveolar macrophages provides an opportunity for determining the mechanism of Tau-Cl action. The effects of Tau-Cl were evaluated on the production of NO and TNF-alpha in NR8383, a cloned cell line derived from rat alveolar macrophages (RAM), and in primary cultures of RAM. Production of NO and TNF-alpha, and expression of inducible NO synthase was inhibited 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-alpha mRNAs was reduced by Tau-Cl in NR8383 cells. Tau-Cl depressed NF-kappaB migration into the nucleus of activated NR8383 cells and caused a more sustained presence of IkappaB in the cytoplasm. Stabilization of cytoplasmic IkappaB-alpha in Tau-Cl-treated cells resulted from decreased phosphorylation of IkappaB-alpha serine-32 and a lower activity of IkappaB kinase (IKK). Additional experiments demonstrated that Tau-Cl does not directly inhibit IKK activity. These results 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-kappaB activation.
Barua
M
M
Department of Developmental Biochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Liu
Y
Y
Quinn
M R
MR
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D051550:I-kappa B Kinase; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013654:Taurine; D009569:Nitric Oxide; C043410:N-chlorotaurine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase