Interleukin-6 participates in human pancreatic stellate cell activation and collagen I production via TGF-β1/Smad pathway

Pancreatic stellate cells (PSCs) play a key role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor-beta 1 (TGF-beta 1) is a major regulator of PSC activation and extracellular matrix production. Interleukin-6 (IL-6) has shown to participate in TGF-beta 1 production and rat PSC activation. This study aimed to investigate whether IL-6 promotes human PSC activation and collagen 1(Col1) production through the TGF-beta 1/Smad pathway. Our results showed that the expression of IL-6 and IL-6R in activated PSCs and macrophages (M phi s) were enhanced in the pancreas of ACP compared to healthy controls and that the mRNA expression of IL-6, IL-6R, TGF-beta 1, alpha-SMA or Col1a1 were significantly increased in the pancreas of ACP, showing positive correlations between elevated IL-6 levels and either TGF-beta 1 or alpha-SMA or Col1a1 levels and between elevated TGF-beta 1 levels and alpha-SMA or Col1a1 levels. In in vitro studies, we identified that IL-6R expression or IL-6 and TGF-beta 1 secretions were significantly increased in, respectively, M phi s and PSCs by ethanol (EtOH) or lipopolysaccharide (LPS) stimulation while EtOH- or LPS-induced alpha-SMA or Col1a1 mRNA and protein production in PSCs were partially blocked by IL-6 antibody. IL-6-induced TGF-beta 1 production in PSCs was antagonized by si-IL6R RNA or by an inhibitor of STAT3. Additionally, IL-6-promoted alpha-SMA or Col1a1 protein production was blocked by TGF-beta 1 antibody and IL-6-induced phosphorylation of Smad2/3 and transcription of alpha-SMA and Col1a1 mRNA were antagonized by si-TGF-beta 1 RNA. Our findings indicate that IL-6 contributes to PSC activation and Col1 production through up-regulation of TGF-beta 1/Smad2/3 pathway.

Automated summary

IL-6 promotes PSC activation and Col1 production through up-regulation of the TGF-beta 1/Smad2/3 pathway, potentially contributing to fibrogenesis in alcoholic chronic pancreatitis.