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Int J Biochem Cell Biol. 2013 Jul;45(7):1366-76. doi: 10.1016/j.biocel.2013.04.003. Epub 2013 Apr 10.

Transcriptional regulation of increased CCL2 expression in pulmonary fibrosis involves nuclear factor-κB and activator protein-1.

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Department of Basic Medical Science, Xiamen University Medical College, Xiamen 361102, Fujian Province, China.


Chemokine (CC motif) ligand-2 (CCL2) is a member of C-C chemokine superfamily that contributes to inflammatory and fibrotic process. Studies in patients and experimental animals provide compelling evidence that increased CCL2 expression plays an important role in the development of fibroproliferative lung disease. The up-regulated CCL2 expression in pulmonary fibrosis is also involved in the potent profibrotic effects that thrombin exerts during lung injury. Here, we investigated the transcriptional mechanism involved in CCL2 production by thrombin in human primary lung fibroblasts and explored the transcriptional mechanism of increased CCL2 expression in pulmonary fibrosis. Thrombin increased CCL2 mRNA levels but not mRNA stability, suggesting it was acting transcriptionally. The increased binding of transcription factors to nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) elements in the CCL2 promoter contributed to active transcription following thrombin stimulation. Primary human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF) produced significantly higher levels of CCL2 than nonfibrotic lung fibroblasts. Furthermore, chromatin immunoprecipitation assays detected increased binding of NF-κB p65 and AP-1 subunit c-Jun to the CCL2 promoter of IPF cells both in the presence and absence of thrombin stimulation. The significantly increased binding of p65 and c-Jun to the CCL2 promoter was also observed in the lung tissue of bleomycin-induced pulmonary fibrosis murine model. Collectively, these findings strongly suggest that the increased binding of transcription factors to NF-κB and AP-1 elements in the CCL2 promoter is responsible for the active transcription expression of CCL2 in pulmonary fibrosis.

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