Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model.
IDO converts tryptophan to l-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, we examined the effect of IDO in α-galactosylceramide (α-GalCer)-induced hepatitis. The increase in IDO expression in the liver of wild-type (WT) mice administered α-GalCer was confirmed by real-time PCR, Western blotting, and IDO immunohistochemical analysis. The serum alanine aminotransferase levels in IDO-knockout (KO) mice after α-GalCer injection significantly increased compared with those in WT mice. 1-Methyl-D-tryptophan also exacerbated liver injury in this murine hepatitis model. In α-GalCer-induced hepatitis models, TNF-α is critical in the development of liver injury. The mRNA expression and protein level of TNF-α in the liver from IDO-KO mice were more enhanced compared with those in WT mice. The phenotypes of intrahepatic lymphocytes from WT mice and IDO-KO mice treated with α-GalCer were analyzed by flow cytometry, and the numbers of CD49b(+) and CD11b(+) cells were found to have increased in IDO-KO mice. Moreover, as a result of the increase in the number of NK cells and macrophages in the liver of IDO-KO mice injected with α-GalCer, TNF-α secretion in these mice was greater than that in WT mice. Deficiency of IDO exacerbated liver injury in α-GalCer-induced hepatitis. IDO induced by proinflammatory cytokines may decrease the number of TNF-α-producing immune cells in the liver. Thus, IDO may suppress overactive immune response in the α-GalCer-induced hepatitis model.
Ito
Hiroyasu
H
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan. hito@gifu-u.ac.jp
Hoshi
Masato
M
Ohtaki
Hirofumi
H
Taguchi
Ayako
A
Ando
Kazuki
K
Ishikawa
Tetsuya
T
Osawa
Yosuke
Y
Hara
Akira
A
Moriwaki
Hisataka
H
Saito
Kuniaki
K
Seishima
Mitsuru
M
D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005699:Galactosylceramides; D006505:Hepatitis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000293:injuries / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D005699:Galactosylceramides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C493154:alpha-galactosylceramide