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KMID : 0425120240620010030
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Parasites, Hosts and Diseases
2024 Volume.62 No. 1 p.30 ~ p.41
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Toxoplasma gondii IST suppresses inflammatory and apoptotic responses by inhibiting STAT1-mediated signaling in IFN-γ/TNF-α-stimulated hepatocytes
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Seo Seung-Hwan
Lee Ji-Eun
Ham Do-Won
Shin Eun-Hee
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Abstract
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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 ofinflammatory molecules in host cells. A sterile inflammatory liver injury in pathologicalacute liver failures occurs when excessive innate immune function, such as the massiverelease 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 atthe 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, STAT1inhibition of TgIST resulted in lower levels of NF-κB and COX2, as well as significantlylower 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. TgISTalso reduced the expression of adhesion (ICAM-1 and VCAM-1) and infiltration markersof 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 resultssuggest that TgIST can inhibit STAT1-mediated inflammatory and apoptotic responsesin hepatocytes stimulated with proinflammatory cytokines.
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KEYWORD
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TgIST, STAT1, acute liver injury, hepatocyte, inflammation, apoptosis
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