Toxoplasma gondii IST suppresses inflammatory and apoptotic responses by inhibiting STAT1-mediated signaling in IFN-γ/TNF-α-stimulated hepatocytes

被引:1
作者
Seo, Seung-Hwan [1 ]
Lee, Ji-Eun [1 ]
Ham, Do-Won [1 ]
Shin, Eun-Hee [1 ,2 ]
机构
[1] Seoul Natl Univ, Inst Endem Dis, Dept Trop Med & Parasitol, Coll Med, Seoul 03080, South Korea
[2] Seoul Natl Univ, Bundang Hosp Med Sci, Seongnam 13620, South Korea
来源
PARASITES HOSTS AND DISEASES | 2024年 / 62卷 / 01期
基金
新加坡国家研究基金会;
关键词
TgIST; STAT1; acute liver injury; hepatocyte; inflammation; apoptosis; RECEPTOR; STAT1; MECHANISMS; EXPRESSION; CYTOKINES; CELLS;
D O I
10.3347/PHD.23129
中图分类号
R38 [医学寄生虫学]; Q [生物科学];
学科分类号
07 ; 0710 ; 09 ; 100103 ;
摘要
The dense granule protein of Toxoplasma gondii, inhibitor of signal transducer and activator of transcription 1 (IST) is an inhibitor of signal transducer and activator of transcription 1 (STAT1) transcriptional activity that binds to STAT1 and regulates the expression of inflammatory molecules in host cells. A sterile inflammatory liver injury in pathological acute liver failures occurs when excessive innate immune function, such as the massive release of IFN-gamma and TNF-alpha, is activated without infection. In relation to inflammatory liver injury, we hypothesized that Toxoplasma gondii inhibitor of STAT1 transcription (TgIST) can inhibit the inflammatory response induced by activating the STAT1/IRF-1 mechanism in liver inflammation. This study used IFN-gamma and TNF-alpha as inflammatory inducers at the cellular level of murine hepatocytes (Hepa-1c1c7) to determine whether TgIST inhibits the STAT1/IRF-1 axis. In stable cells transfected with TgIST, STAT1 expression decreased with a decrease in interferon regulatory factor (IRF)-1 levels. Furthermore, STAT1 inhibition of TgIST resulted in lower levels of NF-KB and COX2, as well as significantly lower levels of class II transactivator (CIITA), iNOS, and chemokines (CLXCL9/10/11). TgIST also significantly reduced the expression of hepatocyte proapoptotic markers (Caspase3/8/9, P53, and BAX), which are linked to sterile inflammatory liver injury. TgIST also reduced the expression of adhesion (ICAM-1 and VCAM-1) and infiltration markers of programmed death-ligand 1 (PD-L1) induced by hepatocyte and tissue damage. TgIST restored the cell apoptosis induced by IFN-gamma/TNF-alpha stimulation. These results suggest that TgIST can inhibit STAT1-mediated inflammatory and apoptotic responses in hepatocytes stimulated with proinflammatory cytokines.
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页码:30 / 41
页数:12
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