CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.

Abstract

BACKGROUND & AIMS:

Several lines of evidence suggest that innate immunity plays a key role in hepatic fibrogenesis. To clarify the role of natural killer (NK) T cells in hepatic inflammation and fibrogenesis, we here investigated xenobiotics-induced liver injury and subsequent fibrogenesis in mice lacking mature NKT cells caused by genetic disruption of the CD1d molecule.

METHODS:

Male CD1d-knockout (KO) and wild-type (WT) mice were given repeated intraperitoneal injections of thioacetamide (TAA, 3times/week; 0.1-0.2mg/g BW) for up to 9 weeks, or a single intraperitoneal injection of CCl(4) (1 μl/g). Liver histology was evaluated, and expression levels of cytokines and matrix-related genes in the liver were quantitatively measured by real-time reverse transcription-polymerase chain reaction (RT-PCR).

RESULTS:

Mortality following repeated injections of TAA was prevented almost completely in CD1d-KO mice. TAA-induced inflammatory responses and hepatocellular damage were markedly ameliorated in CD1d-KO mice. TAA-induced expression of smooth muscle α-actin (SMA) and transforming growth factor (TGF)β1 mRNA in the liver were also prevented largely in CD1d-KO mice. In fact, CD1d-KO mice developed minimal hepatic fibrosis after 9-weeks of administration of TAA, which caused overt bridging fibrosis in WT mice. Indeed, TAA-induced increases in α1(I)procollagen (COL1A1) and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA were blunted significantly in CD1d-KO mice. Similarly, acute CCl(4)-induced hepatic injury and subsequent profibrogenic responses were also reduced significantly in CD1d-KO mice.

CONCLUSIONS:

These findings clearly indicated that CD1d-restricted NKT cells contribute to xenobiotics-induced hepatic inflammation, hepatocellular damage, and subsequent profibrogenic responses in the liver.

• Authors: Sachiko Ishikawa, Kenichi Ikejima, Hisafumi Yamagata, Tomonori Aoyama, Kazuyoshi Kon, Kumiko Arai, Kazuyoshi Takeda, Sumio Watanabe
• Journal: Journal of hepatology (J Hepatol) Vol. 54 Issue 6 Pg. 1195-204 (Jun 2011) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 21145835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antigens, CD1d
• Cd1d1 protein, mouse
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• RNA, Messenger
• Tissue Inhibitor of Metalloproteinase-1
• Thioacetamide

Topics

• Animals
• Antigens, CD1d (genetics, metabolism)
• Base Sequence
• Cell Death (drug effects, immunology)
• Chemical and Drug Induced Liver Injury (etiology, genetics, immunology, pathology)
• Collagen Type I (genetics)
• Collagen Type I, alpha 1 Chain
• Hepatocytes (drug effects, immunology, pathology)
• Immunity, Innate
• Liver Cirrhosis (etiology, genetics, immunology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Natural Killer T-Cells (immunology)
• RNA, Messenger (genetics, metabolism)
• Thioacetamide (toxicity)
• Tissue Inhibitor of Metalloproteinase-1 (genetics)