Mitochondrial-derived oxidants and quartz activation of chemokine gene expression.
Macrophage inflammatory protein 2 (MIP-2) is a chemotactic cytokine which mediates neutrophil recruitment in the lung and other tissues. Pneumotoxic particles such as quartz increase MIP-2 expression in rat lung and rat alveolar type II epithelial cells. Deletion mutant analysis of the rat MIP-2 promoter demonstrated quartz-induction depended on a single NFkappaB consensus binding site. Quartz activation of NFkappaB and MIP-2 gene expression in RLE-6TN cells was inhibited by anti-oxidants suggesting the responses were dependent on oxidative stress. Consistent with anti-oxidant effects, quartz was demonstrated to increase RLE-6TN cell production of hydrogen peroxide. Rotenone treatment of RLE-6TN cells attenuated hydrogen peroxide production, NFkappaB activation and MIP-2 gene expression induced by quartz indicating that mitochondria-derived oxidants were contributing to these responses. Collectively, these findings indicate that quartz and crocidolite induction of MIP-2 gene expression in rat alveolar type II cells results from stimulation of an intracellular signaling pathway involving increased generation of hydrogen peroxide by mitochondria and subsequent activation of NFkappaB.
Driscoll
K E
KE
Procter & Gamble Pharmaceuticals, Health Care Research Center, Mason, Ohio, USA.
Howard
B W
BW
Carter
J M
JM
Janssen
Y M
YM
Mossman
B T
BT
Isfort
R J
RJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D054426:Chemokine CXCL2; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D015846:Monokines / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology; D011791:Quartz / Q000494:pharmacology; D051381:Rats
D000975:Antioxidants; D054426:Chemokine CXCL2; D016166:Free Radical Scavengers; D015846:Monokines; D016328:NF-kappa B; D016877:Oxidants; D011791:Quartz; D006861:Hydrogen Peroxide