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Version of Record online: 8 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 797–805, February 2013
How to Cite
Sahin, H., Borkham-Kamphorst, E., do O, N. T., Berres, M.-L., Kaldenbach, M., Schmitz, P., Weiskirchen, R., Liedtke, C., Streetz, K. L., Maedler, K., Trautwein, C. and Wasmuth, H. E. (2013), Proapoptotic effects of the chemokine, CXCL 10 are mediated by the noncognate receptor TLR4 in hepatocytes. Hepatology, 57: 797–805. doi: 10.1002/hep.26069
Potential conflict of interest: Nothing to report.
This work was supported by grants from the Deutsche Forschungsgemeinschaft (WA 2557/2-1 and SFB/TRR 57 P08; to H.E.W.) and the Else Kröner-Fresenius Stiftung (to H.E.W.).
- Issue online: 5 FEB 2013
- Version of Record online: 8 JAN 2013
- Accepted manuscript online: 19 SEP 2012 11:32AM EST
- Manuscript Accepted: 28 AUG 2012
- Manuscript Received: 23 MAY 2012
Additional Supporting Information may be found in the online version of this article.
|HEP_26069_sm_SuppFig1.tif||1468K||Supplementary Figure 1: Densitometric quantification of p-Akt/Akt ratio in CXCL10 treated hepatocytes within 60 min (A) and within 8 hours (B). *P<0.05, **P<0.01, ***P<0.001. Data are normalized to vehicle-treated control and are expressed as means ± SEM of three independent experiments.|
|HEP_26069_sm_SuppFig2.tif||1590K||Supplementary Figure 2: Densitometric quantification of p-JNK/JNK, cleaved Casp3/β-actin and PAK-2p34/PAK-2 ratio in CXCL10 treated hepatocytes (A). Densitometric quantification of p-Akt/Akt, p-JNK/JNK, cleaved Casp3/β-actin and PAK-2p34/PAK-2 ratio in CXCL10 and Wortmannin treated hepatocytes (B). *P<0.05, **P<0.01, ***P<0.001. Data are normalized to vehicle-treated control and are expressed as means ± SEM of three independent experiments.|
|HEP_26069_sm_SuppFig3.tif||1568K||Supplementary Figure 3: Densitometric quantification of p-Akt/Akt, p-JNK/JNK, cleaved Casp3/β-actin and PAK-2p34/PAK-2 ratio in CXCL10 treated Casp8-/- hepatocytes (A). Densitometric quantification of p-Akt/Akt ratio in CXCL10 treated CXCR3-/- hepatocytes (B). Potential LPS contamination of the recombinant CXCL10 was further assessed by preincubation of CXCL10 with polymyxin B, which inhibits LPS. This preparation did not change CXCL10-mediated Caspase-3 (C) and Akt activation (D). *P<0.05, **P<0.01, ***P<0.001. Data are normalized to vehicle-treated control and are expressed as means ± SEM of three independent experiments.|
|HEP_26069_sm_SuppFig4.tif||1577K||Supplementary Figure 4: Expression of TLR4 on hepatocytes by RT-PCR. 18s was used as reference gene. Control, water (A). Densitometric quantification of p-Akt/Akt ratio in CXCL10 treated TLR4-/- hepatocytes (B). The apoptotic response in Cxcl10 treated wild-type and TLR4-/- mice was also reflected by strongly increased hepatic Caspase-8 activity (C). *P<0.05.|
|HEP_26069_sm_SuppFig5.tif||1106K||Supplementary Figure 5: Proposed CXCL10-induced pathway in hepatocytes Through TLR4, CXCL10 activates PI3K and induces long-term Akt and JNK phosphorylation. Sustained phosphorylation of JNK leads to Caspase-8 and Caspase-3 activation, followed by PAK-2 cleavage. PAK-2p34 fragment translocates to the nucleus and induces apoptosis pathways, while constitutively active (non-cleaved) PAK-2 has been implicated in survival pathways.|
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