Der leberspezifische Wachstumsfaktor Augmenter of liver regeneration wirkt anti-inflammatorisch über STAT3/SOCS3 Inhibition in humanen Hepatozyten

Abstract

Liver withholds the unique capacity to regenerate completely after 70 % resection. For restoring liver mass, an interplay between growth factors and cytokines is involved. Augmenter of liver regeneration (ALR), a liver-specific growth factor, induces proliferation via ras-MAPK/ERK. Interleukin 6 (IL6) plays a crucial role during inflammation and is responsible for activation of signal transducer and activator of transcription 3 (STAT3). STAT3 induces the expression of suppressor of cytokine signaling 3 (SOCS3), a recently discovered key component in down regulating STAT3. The aim of this study is to gain a new insight into the possible anti-inflammatory character of ALR by exploring its correlation to the IL6-induced pathway STAT3/SOCS3. Primary human hepatocytes (phH) and hepatic cell lines (HepG2) were incubated concentration and time-dependent with ALR and/or IL6. Additionally cells were treated with Epidermal Growth Factor (EGF) and Insulin-like-Growth Factor (IGF-I). Western Blot data revealed a more efficient inhibition of STAT3 and SOCS3 after ALR treatment. For studying the corresponding signal pathways MAPK/ERK and PI3K/AKT were inhibited, respectively. Treatment of the cells with PD98059, an ERK specific inhibitor, impaired SOCS3 suppression. Wortmannin pre-incubation, a PI3K/AKT inhibitor, resulted in an abolishment of the inhibitory potential of ALR. Proliferation rate was analyzed by MTT assay and under IL6 treatment a decrease of proliferation was observed. Additional dose dependent ALR donation resulted in a significant increase of proliferation. Based upon these findings, it is concluded that ALR might have a novel discovered anti-inflammatory impact on hepatocytes by inhibition of IL6-induced pathways.