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Superoxide produced by Kupffer cells is an essential effector in concanavalin A–induced hepatitis in mice
Author(s) -
Nakashima Hiroyuki,
Kinoshita Manabu,
Nakashima Masahiro,
Habu Yoshiko,
Shono Satoshi,
Uchida Takefumi,
Shinomiya Nariyoshi,
Seki Shuhji
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22561
Subject(s) - kupffer cell , natural killer t cell , tumor necrosis factor alpha , concanavalin a , cytokine , chemistry , microbiology and biotechnology , immunology , antigen , biology , cd8 , biochemistry , in vitro
Abstract Although concanavalin A (Con‐A)‐induced experimental hepatitis is thought to be induced by activated T cells, natural killer T (NKT) cells, and cytokines, precise mechanisms are still unknown. In the current study, we investigated the roles of Kupffer cells, NKT cells, FasL, tumor necrosis factor (TNF), and superoxide in Con‐A hepatitis in C57BL/6 mice. Removal of Kupffer cells using gadolinium chloride (GdCl 3 ) from the liver completely inhibited Con‐A hepatitis, whereas increased serum TNF and IFN‐γ levels were not inhibited at all. Unexpectedly, anti‐FasL antibody pretreatment did not inhibit Con‐A hepatitis, whereas it inhibited hepatic injury induced by a synthetic ligand of NKT cells, α‐galactosylceramide. Furthermore, GdCl 3 pretreatment changed neither the activation‐induced down‐regulation of NK1.1 antigens as well as T cell receptors of NKT cells nor the increased expression of the CD69 activation antigen of hepatic T cells. CD68 + Kupffer cells greatly increased in proportion in the early phase after Con‐A injection; this increase was abrogated by GdCl 3 pretreatment. Anti‐TNF antibody (Ab) pretreatment did not inhibit the increase of Kupffer cells, but it effectively suppressed superoxide/reactive oxygen production from Kupffer cells and the resulting hepatic injury. Conversely, depletion of NKT cells in mice by NK1.1 Ab pretreatment did suppress both the increase of CD68 + Kupffer cells and Con‐A hepatitis. Consistently, the diminution of oxygen radicals produced by Kupffer cells by use of free radical scavengers greatly inhibited Con‐A hepatitis without suppressing cytokine production. However, adoptive transfer experiments also indicate that a close interaction/cooperation of Kupffer cells with NKT cells is essential for Con‐A hepatitis. Conclusion: Superoxide produced by Kupffer cells may be the essential effector in Con‐A hepatitis, and TNF and NKT cells support their activation and superoxide production. (H EPATOLOGY 2008;48:1979‐1988.)