Superoxide produced by Kupffer cells is an essential effector in concanavalin A-induced hepatitis in mice.

Abstract

UNLABELLED:

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-gamma 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, alpha-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.

• Authors: Hiroyuki Nakashima, Manabu Kinoshita, Masahiro Nakashima, Yoshiko Habu, Satoshi Shono, Takefumi Uchida, Nariyoshi Shinomiya, Shuhji Seki
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 48 Issue 6 Pg. 1979-88 (Dec 2008) ISSN: 1527-3350 [Electronic] United States
• PMID: 18942689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD68 protein, mouse
• Cytokines
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Concanavalin A
• Superoxides
• Interferon-gamma
• Gadolinium
• gadolinium chloride

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Cell Communication
• Chemical and Drug Induced Liver Injury (metabolism, pathology)
• Concanavalin A (adverse effects, pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Gadolinium (pharmacology)
• Interferon-gamma (metabolism)
• Killer Cells, Natural (metabolism, pathology)
• Kupffer Cells (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Reactive Oxygen Species (metabolism)
• Superoxides (metabolism)
• T-Lymphocytes (metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)