Apolipoprotein A-II suppressed concanavalin A-induced hepatitis via the inhibition of CD4 T cell function

• Published in: The Journal of immunology (1950) 2011-03, Vol.186 (6), p.3410-3420
• Main Authors: Yamashita, Junji, Iwamura, Chiaki, Sasaki, Tetsuya, Mitsumori, Kunitoshi, Ohshima, Kazutoshi, Hada, Kaori, Hara, Naoko, Takahashi, Munehisa, Kaneshiro, Yoshiaki, Tanaka, Hitoshi, Kaneko, Kenji, Nakayama, Toshinori
• Format: Article
• Language: English
• Subjects: Animals; Apolipoprotein A-II - deficiency; Apolipoprotein A-II - genetics; Apolipoprotein A-II - therapeutic use; Autoimmune Diseases - chemically induced; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Migration Inhibition - genetics; Cell Migration Inhibition - immunology; Cell Movement - genetics; Cell Movement - immunology; Concanavalin A - antagonists & inhibitors; Concanavalin A - toxicity; Female; Gene Knockout Techniques; Growth Inhibitors - deficiency; Growth Inhibitors - genetics; Growth Inhibitors - therapeutic use; Hepatitis, Animal - chemically induced; Hepatitis, Animal - immunology; Hepatitis, Animal - pathology; Humans; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Mice; Mice, Inbred BALB C; Mice, Knockout
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002924

Con A-induced hepatitis has been used as a model of human autoimmune or viral hepatitis. During the process of identifying immunologically bioactive proteins in human plasma, we found that apolipoprotein A-II (ApoA-II), the second major apolipoprotein of high-density lipoprotein, inhibited the production of IFN-γ by Con A-stimulated mouse and human CD4 T cells. Con A-induced hepatitis was attenuated by the administration of ApoA-II. The beneficial effect of ApoA-II was associated with reduced leukocyte infiltration and decreased production of T cell-related cytokines and chemokines in the liver. ApoA-II inhibited the Con A-induced activation of ERK-MAPK and nuclear translocation of NFAT in CD4 T cells. Interestingly, exacerbated hepatitis was observed in ApoA-II-deficient mice, indicating that ApoA-II plays a suppressive role in Con A-induced hepatitis under physiological conditions. Moreover, the administration of ApoA-II after the onset of Con A-induced hepatitis was sufficient to suppress disease. Thus, the therapeutic effect of ApoA-II could be useful for patients with CD4 T cell-related autoimmune and viral hepatitis.