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.
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.


CONCLUSIONS
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).
Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Maria J
MJ
Perugorria
Lindsay B
LB
Murphy
Nicola
N
Fullard
Jayashree B
JB
Chakraborty
Dimitra
D
Vyrla
Caroline L
CL
Wilson
Fiona
F
Oakley
Jelena
J
Mann
Derek A
DA
Mann
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D007728:Kupffer Cells / Q000166:cytology / Q000502:physiology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
D016207:Cytokines; D011518:Proto-Oncogene Proteins; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse