Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

• Published in: The Journal of immunology (1950) 2004-03, Vol.172 (6), p.3590-3596
• Main Authors: Yamanaka, Atsushi, Hamano, Shinjiro, Miyazaki, Yoshiyuki, Ishii, Kazunari, Takeda, Atsunobu, Mak, Tak W, Himeno, Kunisuke, Yoshimura, Akihiko, Yoshida, Hiroki
• Format: Article
• Language: English
• Subjects: Animals; CD3 antigen; Cell Differentiation - genetics; Cell Differentiation - immunology; Concanavalin A - administration & dosage; Cytokines - biosynthesis; Cytokines - blood; Genetic Predisposition to Disease; Hepatitis, Animal - genetics; Hepatitis, Animal - immunology; Hepatitis, Animal - pathology; IL27R protein; Inflammation Mediators - metabolism; Injections, Intravenous; Interferon-gamma - biosynthesis; Interferon-gamma - physiology; Interleukin-4 - biosynthesis; Interleukin-4 - physiology; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NK1.1 antigen; Receptors, Cytokine - deficiency; Receptors, Cytokine - genetics; Receptors, Cytokine - physiology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Up-Regulation - genetics; Up-Regulation - immunology; WSX-1 protein
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.6.3590

Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-gamma and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-gamma and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-alpha, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.