Phosphorylation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and nuclear translocation of nuclear factor-κB are involved in upregulation of matrix metalloproteinase-9 by tumour necrosis factor-α
Article first published online: 15 AUG 2008
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd
Volume 29, Issue 2, pages 291–298, February 2009
How to Cite
Itatsu, K., Sasaki, M., Harada, K., Yamaguchi, J., Ikeda, H., Sato, Y., Ohta, T., Sato, H., Nagino, M., Nimura, Y. and Nakanuma, Y. (2009), Phosphorylation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and nuclear translocation of nuclear factor-κB are involved in upregulation of matrix metalloproteinase-9 by tumour necrosis factor-α. Liver International, 29: 291–298. doi: 10.1111/j.1478-3231.2008.01858.x
- Issue published online: 6 JAN 2009
- Article first published online: 15 AUG 2008
- Received 15 January 2008Accepted 7 July 2008
- matrix metalloproteinase;
- tumour necrosis factor-α
Background: Upregulation of matrix metalloproteinase-9 (MMP-9) induced by tumour necrosis factor-α (TNF-α) is reportedly involved in a variety of non-neoplastic and neoplastic diseases. In this study, we examined which signalling pathways are involved in TNF-α-induced MMP-9 upregulation in cholangiocarcinoma (CC).
Methods: We used two CC cell lines: HuCCT-1 and CCKS-1.
Results: In an ex vivo study using HuCCT-1 and CCKS-1 cells, TNF-α treatment induced MMP-9 production and activation via interaction with TNF receptor-1 (TNF-R1) but not with TNF receptor-2 (TNF-R2), shown by zymography, and increased MMP-9 promoter activity (luciferase assay). As for the signalling pathway, TNF-α stimulation led to the phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and p38 mitogen-activated protein kinase (p38MAPK) and translocation of nuclear factor κB (NF-κB) (p65) into the nuclei. Inhibition studies using SB203580 (inhibitor of p38MAPK), U0126 (inhibitor of mitogen-activated or extracellular signal-regulated protein kinase 1/2) and MG132 (inhibitor of NF-κB) showed that the phosphorylation of Erk1/2 and p38MAPK with activation of NF-κB was closely related to MMP-9 upregulation in both cell lines.
Conclusion: These data suggest that TNF-α/TNF-R1 interaction leads to the phosphorylation of Erk1/2 and p38MAPK and nuclear translocation of NF-κB, which is closely associated with the production and activation of MMP-9 in cultured CC cells of HuCTT-1 and CCKS-1. Upregulation of MMP-9 with NF-κB activation may be involved in the tumour invasion of CC.