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Lipopolysaccharide-induced acute inflammation protects mice from Fas-mediated apoptosis through Stat3 dependent pathway (CROSBI ID 668156)

Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | domaća recenzija

Markotić, Antonio ; Flegar, Darja ; Grčević, Danka ; Šućur, Alan ; Lalić, Hrvoje ; Kovačić, Nataša ; Turčić, Petra ; Pravdić, Danijel ; Šisl, Dino ; Ćavar, Ivan et al. Lipopolysaccharide-induced acute inflammation protects mice from Fas-mediated apoptosis through Stat3 dependent pathway // 2018 ANNUAL MEETING OF THE CROATIAN IMMUNOLOGICAL SOCIETY. Book of Abstracts. 2018. str. 53-53

Podaci o odgovornosti

Markotić, Antonio ; Flegar, Darja ; Grčević, Danka ; Šućur, Alan ; Lalić, Hrvoje ; Kovačić, Nataša ; Turčić, Petra ; Pravdić, Danijel ; Šisl, Dino ; Ćavar, Ivan ; Kelava, Tomislav

engleski

Lipopolysaccharide-induced acute inflammation protects mice from Fas-mediated apoptosis through Stat3 dependent pathway

Introduction: Apoptosis is increasingly recognized as one of the crucial mechanisms in liver injury. It is involved in both, chronic liver diseases and acute liver injuries. However, the nature of inflammation-apoptosis crosstalk in liver is still under research. As we had previously found that acute inflammation induced by lipopolysaccharide (LPS) protects mice from Fas-mediated apoptosis, we aimed to explore if the observed protective effect is mediated by Janus kinase (JAK)/Stat3 signaling pathway. Materials and Methods: Male C57BL/6 mice were treated with ruxolitinib, selective JAK1/2 inhibitor, (double oral gavage with 2 hours between applications, to a final dose of 180 mg/kg) or vehicle (Peg300/DMSO/dH2O) followed by intraperitoneal injection of LPS (0.025 µg/g) 2 hours after. Liver samples were harvested after 90 minutes and phosphorylated Stat3 (pStat3) and Stat3 expressions were determined (western blot). The gene expression of proinflammatory cytokines and apoptosis-related factors were analyzed (qPCR). Liver specimens were also collected from LPS or saline treated mice (2 hours after treatment) for immunohistochemistry (pStat3). To explore the possible involvement of JAK/Stat3 pathway in the anti-apoptotic effect of the inflammation, mice were treated with ruxolitinib or vehicle, followed by LPS and anti- Fas (JO2) activating antibody (0.25 μg/g, intravenously) 2 hours after LPS. Sera were collected 6 hours after anti-Fas application for ALT measurement. Results: LPS treatment induced the phosphorylation of Stat3 in hepatocytes. Immunoblots revealed an increase in pStat3 expression in liver samples after LPS treatment, while immunohistochemical analysis showed an increase in pStat3 positive hepatocytes when compared to saline treated mice. Ruxolitinib pretreatment successfully inhibited the LPS- induced expression of pStat3 and densitometry showed significantly lower pStat3/Stat3 ratio in ruxolitinib/LPS treated mice in comparison with vehicle/LPS group (p=0.008). Finally, in vivo experiments showed that ruxolitinib pretreatment abrogates the anti-apoptotic effect of LPS. Ruxolitinib/LPS/anti-Fas treated mice had significantly higher levels of ALT when compared with vehicle/LPS/anti-Fas treated group (median [IQR]: 800.0 [532.5-1190] vs. 175.0 [57.5-442.5] IU/L respectively ; p=0.026). Ruxolitinib did not aggravate the anti-Fas induced apoptosis as determined by ALT levels (ruxolitinib/anti-Fas vs. vehicle/anti-Fas, p=0.57). Interestingly, ruxolitinib pretreatment augmented the LPS-induced gene expression of proinflammatory cytokines (TNF- alpha, IL-1 and IL-6), and significantly reduced the expression of Bcl-xL in comparison with LPS treated mice (p=0.02). Conclusion: Acute inflammation induced by LPS protects mice from Fas-mediated liver injury. Stat3 could be one of the crucial mediators involved in this protective effect, as ruxolitinib-induced inhibition of JAK signaling significantly reversed the anti- apoptotic feature of LPS.

Fas ; LPS ; Liver ; Apoptosis

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Podaci o prilogu

53-53.

2018.

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objavljeno

Podaci o matičnoj publikaciji

2018 ANNUAL MEETING OF THE CROATIAN IMMUNOLOGICAL SOCIETY. Book of Abstracts

Podaci o skupu

Annual meeting of the Croatian Immunological Society 2018

poster

19.10.2018-20.10.2018

Zadar, Hrvatska

Povezanost rada

nije evidentirano

Poveznice