Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
0192623309336153v1
37/4/536    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Kumagai, K.
Right arrow Articles by Manabe, S.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kumagai, K.
Right arrow Articles by Manabe, S.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Articles

Neutralization of IL-10 Exacerbates Cycloheximide-Induced Hepatocellular Apoptosis and Necrosis

Kazuyoshi Kumagai1, Kazumi Ito1, Yosuke Ando1, Shinobu Hakamata1, Munehiro Teranishi1, Hiroyuki Nakayama2 and Sunao Manabe1

1 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Fukuroi, Shizuoka 437-0065, Japan
2 Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan

Correspondence: Kazuyoshi Kumagai, Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan; e-mail:kumagai.kazuyoshi.k6{at}daiichisankyo.co.jp.

Cycloheximide (CHX)-induced liver injury in rats has been characterized by hepatocellular apoptosis and necrosis. We previously reported that Kupffer cell inactivation causes a reduction of IL-10 production, resulting in the exacerbation of CHX-induced liver injury. In this study, we directly evaluate the role of IL-10 in liver injury by a pretreatment with anti-IL-10 neutralizing antibody (IL-10Ab). Rats were given goat IgG or IL-10Ab before being treated with CHX (CHX group or IL-10Ab/CHX group). In the CHX group, the CHX treatment markedly induced hepatic mRNA and serum protein levels of IL-10. The up-regulation of IL-10 was significantly suppressed in the IL-10Ab/CHX group. Blocking IL-10 in the IL-10Ab/ CHX group led to greater increases in hepatic mRNA and serum levels of proinflammatory cytokines, such as TNF-{alpha} and IL-6. The IL-10Ab/CHX group developed more severe hepatocellular apoptosis, neutrophil transmigration, and necrotic change of hepatocytes compared with the CHX group. The caspase activities and mRNA levels of Cc120, LOX-1, and E-selectin in the livers were significantly higher in the IL-10Ab/CHX group than the CHX group. These results demonstrate that IL-10 plays an important role in counteracting the effect of proinflammatory cytokines, such as a TNF signaling cascade, and in attenuating the CHX-induced liver injury.

Key Words: cycloheximide • interleukin-10 • apoptosis • neutralizing antibody • liver

Abbreviations: ALT, alanine aminotransferase; • AST, aspartate aminotransferase; • Ccl, chemokine ligand; • CHX, cycloheximide; • GdCl3, gadolinium chloride; • IL, interleukin; • LOX-1, oxidized low-density lipoprotein (lectin-like) receptor 1.

This version was published on June 1, 2009

Toxicologic Pathology, Vol. 37, No. 4, 536-546 (2009)
DOI: 10.1177/0192623309336153
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?