Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-κB-dependent pathways

• Published in: Journal of hepatology Vol. 51; no. 1; pp. 139 - 148
• Main Authors: Jiang, Joy X, Mikami, Kenichiro, Venugopal, Senthil, Li, Yong, Török, Natalie J
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.07.2009; Elsevier
• Subjects: Apoptosis; Biological and medical sciences; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Liver fibrogenesis; Medical sciences; NADPH oxidase; Oxidative radicals; Phagocytosis; AB; hepatic stellate cells; α-smooth muscle actin; carboxytetramethyl rhodamine succinimidyl ester; TAMRA; Liver fibrogenesis; NADPH oxidase; ASMA; HSC; TGF-β1; transforming growth factor-β1; Oxidative radicals; Phagocytosis; apoptotic bodies; Apoptosis; nicotinamide adenine dinucleotide phosphate reduced oxidase; Spider cell; Prognosis; Enzyme; Liver; Oxidase; Survival; Gastroenterology; Oxidoreductases; Transcription factor NFκB
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2009.03.024

Background/Aims We have previously shown that phagocytosis of apoptotic bodies (AB) by hepatic stellate cells (HSC) is profibrogenic. As HSC survival is central to the progression of liver fibrosis, our goal was to investigate if phagocytosis induces HSC survival. Methods Apoptosis of phagocytosing HSC was studied in the presence of known apoptotic agents. The JAK/STAT- and PI3K/Akt-dependent pathways, NF-κB activation and expression of the anti-apoptotic proteins Mcl-1 and A1 were evaluated. Apoptosis was assessed after blocking A1 by an siRNA approach. Results Phagocytosing HSC were resistant to FasL/cycloheximide or TRAIL-induced apoptosis. Inhibition of the JAK/STAT or PI3K-mediated pathways induced apoptosis of HSC. Phagocytosis induced JAK1/STAT3 phosphorylation, and this was prevented by inhibiting JAK. Translocation of STAT3 to the nucleus was also blocked by JAK inhibition. Mcl-1 expression was upregulated in a JAK-dependent manner. PI3K-dependent phosphorylation of Akt depended on NADPH oxidase activity and superoxide production. NF-κB activation and subsequent upregulation of A1 was observed, and A1 inhibition induced apoptosis of HSC. Conclusion Phagocytosis of AB promotes HSC survival by two pathways, of which the A1 dependent is more significant. This represents a new mechanism by which engulfment of AB contributes to the propagation of liver fibrosis.