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.
Department of Oral Molecular Regulation, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, Japan.
Yuko
Y
Ohtaki
Kouji
K
Yamaguchi
Zhiqian
Z
Yu
Hiroyuki
H
Kumamoto
Hidetoshi
H
Shimauchi
Yoichiro
Y
Iwakura
Shunji
S
Sugawara
Yasuo
Y
Endo
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