Superoxide produced by Kupffer cells is an essential effector in concanavalin A–induced hepatitis in mice
✍ Scribed by Hiroyuki Nakashima; Manabu Kinoshita; Masahiro Nakashima; Yoshiko Habu; Satoshi Shono; Takefumi Uchida; Nariyoshi Shinomiya; Shuhji Seki
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 525 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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-␥ 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, ␣-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. (HEPATOLOGY 2008;48:1979-1988.) I t is well known that severe hepatic injury is induced after Concanavalin A (Con-A ) administration into mice. This experimental hepatitis model, which was discovered by Tiegs et al. 1 in 1992, is accompanied by a remarkable activation of T cells. Considering the indispensable involvement of CD4-positive T cells, Con-A hepatitis has been regarded as a model of T cell-mediated autoimmune hepatitis. 1 Since the discovery of Con-A hepatitis, a number of studies have been published. Among the wide range of cytokines, the critical role of tumor necrosis factor (TNF) in Con-A hepatitis was proved by experiments using anti-TNF antibody (Ab). [2][3][4] It was also reported that interferon gamma (IFN-␥) participates strongly in the manifestation of hepatotoxicity. 5,6 In previous reports, natural killer T cells (NKT cells) were suggested to play a major role in this hepatitis model. [7][8][9] Considering that this hepatitis does not develop well