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Article first published online: 28 FEB 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 3, pages 1238–1249, March 2013
How to Cite
Perugorria, M. J., Murphy, L. B., Fullard, N., Chakraborty, J. B., Vyrla, D., Wilson, C. L., Oakley, F., Mann, J. and Mann, D. A. (2013), Tumor progression locus 2/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptor–induced TIMP-1 gene transcription in hepatic stellate cells in mice. Hepatology, 57: 1238–1249. doi: 10.1002/hep.26108
Potential conflict of interest: Nothing to report.
The present study was supported by the Wellcome Trust (grant no.: WT086755MA) and a European Commission FP7 program grant “INFLA-CARE” (EC contract no.: 223151; http://inflacare.imbb.forth.gr/) (both to D.A.M.). The authors thank Dr. Steven C Ley (MRC National Institute for Medical Research, London, UK) for the generous gift of Tpl2−/− mice.
- Issue published online: 28 FEB 2013
- Article first published online: 28 FEB 2013
- Accepted manuscript online: 18 OCT 2012 12:00AM EST
- Manuscript Accepted: 9 OCT 2012
- Manuscript Received: 30 JUN 2012
Toll-like receptors (TLRs) function as key regulators of liver fibrosis and are able to modulate the fibrogenic actions of nonparenchymal liver cells. The fibrogenic signaling events downstream of TLRs on Kupffer cells (KCs) and hepatic stellate cells (HSCs) are poorly defined. Here, we describe the MAP3K tumor progression locus 2 (Tpl2) as being important for the activation of extracellular regulated kinase (ERK) signaling in KCs and HSCs responding to stimulation of TLR4 and TLR9. KCs lacking Tpl2 display defects with TLR induction of cytokines interleukin (IL)-1β, IL-10, and IL-23. tpl2−/− HSCs were unable to increase expression of fibrogenic genes IL-1β and tissue inhibitor of metalloproteinase 1 (TIMP-1), with the latter being the result of defective stimulation of TIMP-1 promoter activity by TLRs. To determine the in vivo relevance of Tpl2 signaling in liver fibrosis, we compared the fibrogenic responses of wild-type (WT) and tpl2−/− mice in three distinct models of chronic liver injury. In the carbon tetrachloride and methionine-choline–deficient diet models, we observed a significant reduction in fibrosis in mice lacking Tpl2, compared to WT controls. However, in the bile duct ligation model, there was no effect of tpl2 deletion, which may reflect a lesser role for HSCs in wounding response to biliary injury. Conclusion: We conclude that Tpl2 is an important signal transducer for TLR activation of gene expression in KCs and HSCs by the ERK pathway and that suppression of its catalytic activity may be a route toward suppressing fibrosis caused by hepatocellular injuries. (HEPATOLOGY 2013)