Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis.
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.
Yamanaka
Atsushi
A
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Hamano
Shinjiro
S
Miyazaki
Yoshiyuki
Y
Ishii
Kazunari
K
Takeda
Atsunobu
A
Mak
Tak W
TW
Himeno
Kunisuke
K
Yoshimura
Akihiko
A
Yoshida
Hiroki
H
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003208:Concanavalin A / Q000008:administration & dosage*; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D020022:Genetic Predisposition to Disease; D006520:Hepatitis, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D018123:Receptors, Interleukin; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; C484747:Il27ra protein, mouse; D018836:Inflammation Mediators; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma