Parasites, Hosts and Diseases

The Korea Society for Parasitology and Tropical Medicine (대한기생충학·열대의학회)
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Toxoplasma gondii IST suppresses inflammatory and apoptotic responses by inhibiting STAT1-mediated signaling in IFN-γ/TNF-α-stimulated hepatocytes

  • Seung-Hwan Seo (Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, Institute of Endemic Diseases) ;
  • Ji-Eun Lee (Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, Institute of Endemic Diseases) ;
  • Do-Won Ham (Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, Institute of Endemic Diseases) ;
  • Eun-Hee Shin (Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, Institute of Endemic Diseases)
  • Received : 2023.12.29
  • Accepted : 2024.01.29
  • Published : 2024.02.29
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Abstract

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-γ and TNF-α, 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-γ and TNF-α 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-κB 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-γ/TNF-α stimulation. These results suggest that TgIST can inhibit STAT1-mediated inflammatory and apoptotic responses in hepatocytes stimulated with proinflammatory cytokines.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (No. NRF-2022R1A2C1009234) and also by grant no. 02-2022-0009 from the Seoul National University Bundang Hospital (SNUBH) Research Fund.

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