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Protective effects of HFE7A, mouse anti-human/mouse Fas monoclonal antibody against acute and lethal hepatic injury induced by Jo2

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Abstract

HFE7A is a mouse anti-human/mouse Fas monoclonal antibody which, protects mice from fulminant hepatitis induced by Jo2. Herein, we report on the mechanism of the protective effect of HFE7A against Jo2-induced acute and lethal hepatic injury. HFE7A reduced the serum aminotransferase level which was elevated after Jo2 injection. HFE7A also inhibited caspase activation and mitochondrial depolarization in hepatocytes derived from apoptosis induced by Jo2 injection. The protective effect of HFE7A against Jo2-induced apoptosis in mouse hepatocytes was reproducible in vitro. The cell death and caspase activation in isolated mouse hepatocytes were induced by incubating these cells with Jo2 in vitro, and HFE7A inhibited the cell death and caspase activation in mouse hepatocytes in a dose-dependent manner. The affinity of HFE7A to mouse Fas was lower than that of Jo2. The binding of Jo2 to neither recombinant mouse Fas nor mouse hepatocytes was inhibited by an excessive amount of HFE7A. Interestingly, HFE7A bound to hepatocytes isolated from Fas knockout mice. From these results, it is suggested that HFE7A may exert a protective effect against Jo2-induced hepatitis not by competitively inhibiting the binding of Jo2 to Fas on hepatocytes, and that a distinct molecule other than Fas may possibly be involved in the protective effect of HFE7A against Jo2-induced hepatic injury.

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Abbreviations

TNF:

Tumor necrosis factor

NGF:

Nerve growth factor

FasL:

Fas ligand

mAb:

Monoclonal antibody

HTLV-I:

Human T cell leukemia virus type I

RA:

Rheumatoid arthritis

SCID:

Severe combined immunodeficient

i.v.:

Intravenously

i.p.:

Intraperitoneally

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

LDH:

Lactose dehydrogenase

NO:

Nitric oxide

DISC:

Death inducing signaling complex

MORT:

Mediator of receptor-induced toxicity

FADD:

Fas-associated protein with death domain

DR:

Death receptor

COX:

Cyclooxygenase

FcγRII:

Fcγ receptor II

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Acknowledgments

We would like to thank Dr. Shin Yonehara (Graduate School of Biostudies, Kyoto University) for kindly providing the Fas knockout mice and for the helpful discussions and also Dr. Jun Ohsumi (Biological Research Laboratories II, Daiichi Sankyo Co., Ltd.) for the helpful discussions. We are also grateful to Dr. Manabu Abe, Ms. Yumiko Fujisawa (Biological Research Laboratories II, Daiichi Sankyo Co., Ltd.), and Ms. Akiko Oguni (Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd.) for their technical support.

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Authors and Affiliations

  1. Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd., Tokyo, 134-8630, Japan

    Hiroko Yoshida & Kimihisa Ichikawa

  2. Exploratory Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, 134-8630, Japan

    Kenji Watanabe

  3. Biologics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, 134-8630, Japan

    Shu Takahashi

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  1. Hiroko Yoshida
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  2. Kenji Watanabe
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  3. Shu Takahashi
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  4. Kimihisa Ichikawa
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Correspondence to Hiroko Yoshida.

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Yoshida, H., Watanabe, K., Takahashi, S. et al. Protective effects of HFE7A, mouse anti-human/mouse Fas monoclonal antibody against acute and lethal hepatic injury induced by Jo2. Cytotechnology 62, 313–323 (2010). https://doi.org/10.1007/s10616-009-9244-6

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  • DOI: https://doi.org/10.1007/s10616-009-9244-6

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