Depletion of apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced necroinflammation and subsequent peribiliary fibrosis.

Abstract

Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bile duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK1-deficient (ASK1(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK1(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK1(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK1(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribiliary fibrogenic cells and peribiliary fibrosis. These observations indicate that ASK1-mediated hepatic necroinflammation and proliferation, but not apoptosis, are closely linked to liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.

• Authors: Hirotsugu Noguchi, Sohsuke Yamada, Atsunori Nabeshima, Xin Guo, Akihide Tanimoto, Ke-Yong Wang, Shohei Kitada, Takashi Tasaki, Tatsuo Takama, Shohei Shimajiri, Hasita Horlad, Yoshihiro Komohara, Hiroto Izumi, Kimitoshi Kohno, Hidenori Ichijo, Yasuyuki Sasaguri
• Journal: The American journal of pathology (Am J Pathol) Vol. 184 Issue 3 Pg. 644-61 (Mar 2014) ISSN: 1525-2191 [Electronic] United States
• PMID: 24412091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• MAP Kinase Kinase Kinase 5
• MAP Kinase Kinase Kinases
• Map3k5 protein, mouse

Topics

• Animals
• Apoptosis
• Bile Ducts (pathology)
• Cell Proliferation
• Cholestasis (pathology)
• Hepatocytes (metabolism)
• Inflammation
• Liver (metabolism)
• Liver Cirrhosis (metabolism, pathology)
• MAP Kinase Kinase Kinase 5 (genetics, metabolism)
• MAP Kinase Kinase Kinases (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Sequence Deletion
• Signal Transduction