Copper activates the NF-kappaB pathway in vivo.
Previous results indicated that intravenous injection of copper in the form of a copper-histidine complex in rats triggers the transcriptional induction of the inducible form of nitric oxide synthase (NOS-II). Here, the authors demonstrate that copper activates the transcription factor NF-kappaB in the liver and lung tissues of rats, and that this effect is mediated by oxidative stress, since all copper-induced changes, which include histological alterations, formation of nitrotyrosines, vascular pressure drop, production of tumor necrosis factor-alpha (TNF-alpha), induction of NOS-II and nitrites, are readily prevented by pretreatment of the animals with the antioxidant tempol. By using electrophoretic mobility shift assays, the p50/p65 dimer and higher molecular weight aggregates have been found to be involved in the copper-induced NF-kappaB activation. COX-2, a NF-kappaBdependent gene involved in the inflammatory response, was also transcriptionally induced by copper, this effect being reduced in the presence of tempol. These results suggest that a physiopathological status, characterized by hypercupremic situations, may lead to the onset of inflammation through production of ROS and activation of NF-kappaB.
Persichini
Tiziana
T
Dipartimento di Biologia, Università Roma Tre, Rome, Italy.
Percario
Zulema
Z
Mazzon
Emanuela
E
Colasanti
Marco
M
Cuzzocrea
Salvatore
S
Musci
Giovanni
G
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003300:Copper / Q000008:administration & dosage / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006639:Histidine / Q000031:analogs & derivatives / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D009942:Organometallic Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013113:Spin Labels; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000975:Antioxidants; D003497:Cyclic N-Oxides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009566:Nitrates; D009573:Nitrites; D009942:Organometallic Compounds; D012333:RNA, Messenger; D013113:Spin Labels; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D006639:Histidine; D003300:Copper; C098468:copper histidine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C001803:tempol