Naslov
LPS‐induced inflammation desensitizes hepatocytes to Fas‐ induced apoptosis through Stat3 activation—The effect can be reversed by ruxolitinib

Autori
Markotić, Antonio ; Flegar, Darja ; Grčević, Danka ; Šućur, Alan ; Lalić, Hrvoje ; Turčić, Petra ; Kovačić, Nataša ; Lukač, Nina ; Pravdić, Danijel ; Vukojević, Katarina ; Ćavar, Ivan ; Kelava, Tomislav

Izvornik
Journal of cellular and molecular medicine (1582-1838) 24 (2020), 5; 2981-2992

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
apoptosis ; Fas ; lipopolysaccharide ; ruxolitinib ; Stat3

Sažetak
Recent studies have established a concept of tumour necrosis factor-α (TNF-α)/Fas signalling crosstalk, highlighting TNF-α as a critical cytokine in sensitizing hepatocytes to death induced by Fas activation. However, in the exact inflammatory response, besides TNF-α, many other mediators, that might modulate apoptotic response differentially, are released. To resolve the issue, we studied the effects of lipopolysaccharide (LPS), one of the crucial inductors of inflammation in the liver, on apoptotic outcome. We show that LPS-induced inflammation diminishes the sensitivity of hepatocytes to Fas stimulus in vivo at caspase-8 level. Analysis of molecular mechanisms revealed an increased expression of various pro- inflammatory cytokines in non- parenchymal liver cells and hepatocyte-specific increase in Bcl- xL, associated with signal transducer and activator of transcription 3 (Stat3) phosphorylation. Pre- treatment with ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, prevented the LPS- induced Stat3 phosphorylation and restored the sensitivity of hepatocytes to Fas-mediated apoptosis. Furthermore, ruxolitinib pre-treatment diminished the LPS-induced Bcl-xL up-regulation without an inhibitory effect on LPS-induced expression of pro- inflammatory cytokines. In summary, although the reports are showing that the effects of isolated pro-inflammatory mediators, such as TNF-α or neutrophils, are pro- apoptotic, the overall effect of inflammatory milieu on hepatocytes in vivo is Stat3-dependent desensitization to Fas-mediated apoptosis.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA