STAT-1 signaling in human lung fibroblasts is induced by vanadium pentoxide through an IFN-β autocrine loop

被引:30
作者
Antao-Menezes, Aurita [2 ]
Turpin, Elizabeth A. [2 ]
Bost, Phillip C. [1 ]
Ryman-Rasmussen, Jessica P. [1 ,2 ]
Bonner, James C. [1 ,2 ]
机构
[1] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA
[2] Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.4049/jimmunol.180.6.4200
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The inhalation of vanadium pentoxide (V2O5) results in bronchitis and airway fibrosis. The lung fibrotic response to V2O5 partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis. We previously reported that STAT-1 is a protective factor and mice lacking STAT-1 are more susceptible to lung fibrosis. We also reported that V2O5-induced STAT-1 phosphorylation in lung fibroblasts requires H2O2 and de novo protein synthesis. In this study, we identified IFN-beta as the protein that mediates STAT-1 activation by V2O5 in normal human lung fibroblasts and identified NADPH and xanthine oxidase systems as sources of H2O2 that drive IFN-beta gene expression. STAT-1 phosphorylation was decreased with neutralizing Abs to IFN-beta as well as an inhibitor of JAK. V2O5 also increased transcription of an IFN-inducible and STAT-1-dependent chemokine, CXCL10. Inhibition of H2O2-generating enzyme systems NADPH oxidase by apocynin and xanthine oxidase by allopurinol individually reduced STAT-1 phosphorylation. Apocynin and allopurinol also decreased V2O5-induced IFN-beta mRNA levels and CXCL10 expression. IFN-alpha transcription was inhibited only by allopurinol. Taken together, these data indicate that fibroblasts play a role in the innate immune response to vanadium-induced oxidative stress by synthesizing IFN-beta and activating STAT-1 to cause growth arrest and increase levels of CXCL10, a potent antifibrotic factor. This mechanism is postulated to counterbalance profibrogenic mechanisms that follow V2O5 injury.
引用
收藏
页码:4200 / 4207
页数:8
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