Hepatic platelet accumulation in Fas-mediated hepatitis in mice

Yuko Ohtaki, Kouji Yamaguchi, Zhiqian Yu, Hiroyuki Kumamoto, Hidetoshi Shimauchi, Yoichiro Iwakura, Shunji Sugawara, Yasuo Endo

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Platelets are reported to be causally involved in experimental hepatitis. Jo2, an agonistic anti-Fas antibody, induces hepatitis in mice. We examined the in vivo behaviors of platelets in mice injected with this antibody (analyzed by measuring 5-hydroxytryptamine, a constituent of platelets). We found that Jo2 induces platelet accumulation predominantly in the liver, and that this hepatic platelet accumulation (HPA) precedes the increases in hepatitis markers (alanine- and asparagine-aminotransferases [ALT and AST]). By electron microscopy, we detected entry of platelets into hepatocytes, and also evidence of apoptosis among hepatocytes. A caspases-3/6/7/8/10 inhibitor prevented the Jo2-induced HPA and hepatitis. In platelet-depleted mice, contrary to our expectations, the Jo2-induced hepatitis was not reduced, and actually the increase in AST was significantly augmented, although the survival time of mice given a lethal dose of Jo2 was significantly increased (nearly doubled). Interestingly, prior induction of HPA by a low dose of lipopolysaccharide markedly reduced Jo2-induced hepatitis. Jo2 also induced HPA and hepatitis in mice deficient in both IL-1 and TNFα, although Jo2 increased the blood level of TNFα in wild-type mice. These results suggest that in Jo2-induced hepatitis: (i) platelets accumulate predominantly in the liver as a result of hepatic lesions, and that this precedes the release of transaminases from hepatocytes, and (ii) IL-1 and TNFα are not essential for Jo2-hepatitis. We hypothesize that platelet accumulation in the liver may, contrary to our expectations, be protective when the hepatitis is local or not severe, but harmful when hepatitis is severe.

Original languageEnglish
Pages (from-to)1071-1078
Number of pages8
JournalInternational Immunopharmacology
Volume9
Issue number9
DOIs
Publication statusPublished - 2009 Aug

Keywords

  • Apoptosis
  • Fas
  • Hepatitis
  • Liver
  • Platelets

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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