Hepatic platelet accumulation in Fas-mediated hepatitis in mice.
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 TNFalpha, although Jo2 increased the blood level of TNFalpha 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 TNFalpha 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.
Ohtaki
Yuko
Y
Department of Oral Molecular Regulation, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, Japan.
Yamaguchi
Kouji
K
Yu
Zhiqian
Z
Kumamoto
Hiroyuki
H
Shimauchi
Hidetoshi
H
Iwakura
Yoichiro
Y
Sugawara
Shunji
S
Endo
Yasuo
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D053582:Interleukin-1alpha / Q000097:blood / Q000235:genetics; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D047589:Leukocyte Reduction Procedures; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008854:Microscopy, Electron; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015415:Biomarkers; C491899:Fas protein, mouse; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000410:Alanine Transaminase; D020169:Caspases