Abstract
Inflammation has an important role in the development of liver fibrosis in general and the activation of hepatic stellate cells (HSCs) in particular. It is known that HSCs are themselves able to produce cytokines and chemokines, and that this production may be a key event in the initiation of fibrogenesis. However, the direct involvement of cytokines and chemokines in HSC (self-)activation remains uncertain. In this study, the effects of pro-inflammatory cytokines IL-1α and β, TNF-α, and IL-8 on the activation state of HSCs were examined, in comparison to the pro-fibrogenic mediator TGF-β1. LX-2 cells were stimulated for 24 or 48 hours with recombinant human form of the pro-inflammatory cytokines IL-1α and β, TNF-α, and IL-8, and also the pro-fibrogenic mediator TGF-β1. Two drugs were also evaluated, the anti-TNF-α monoclonal antibody infliximab and the IL-1 receptor antagonist anakinra, regarding their inhibitory effects. In LX-2 human HSC, treatment with TGF-β1 are associated with downregulation of the metalloproteinase (MMP)-1 and MMP-3, with upregulation of tissue inhibitor of metalloproteinase (TIMP)-1, collagen type I α1, collagen type IV α1, α-SMA, endothelin-1 and PDGF-BB. Cytokines and chemokines expression were found to be downregulated, excepting IL-6. In contrast, we observed that LX-2 exposure to IL-1, TNF-α and IL-8 can reverse the phenotype of pro-fibrogenic activated cells. Indeed, MMP-1, MMP-3 and MMP-9 were found elevated, associated with downregulation of α-SMA and/or PDGF-BB, and a greater expression of IL-1β, IL-6, IL-8, CXCL1 and CCL2. Lastly, we found that infliximab and anakinra successfully inhibits effects of TNF-α and IL-1 respectively in LX-2 cells. Infliximab and anakinra may be of value in preclinical trials in chronic liver disease. Overall, our results suggest that (i) pro-inflammatory mediators exert complex effects in HSCs via an MMP/TIMP imbalance, and (ii) targeting IL-1 signaling may be a potentially valuable therapeutic strategy in chronic liver diseases.
Highlights
Fibrosis is a common pathologic consequence of a wide variety of chronic liver diseases, including hepatitis B and C virus infections, alcoholic liver disease and nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis (NAFLD/NASH), and results from an accumulation of extracellular matrix (ECM) following the activation and proliferation of hepatic stellate cells (HSCs)
Treatment with rhTGF-β1 was associated with lower mRNA levels of pro-inflammatory cytokines (IL-1β, TNF-α and IL-8) and the neutrophil chemoattractant CXCL1, and higher mRNA levels of IL-6 and the monocyte chemoattractant CCL2 (Fig 1C)
These results were confirmed at protein levels by ELISA in which IL-8 release was downregulated and IL-6 release upregulated after 24 hours treatment with rhTGF-β1
Summary
Fibrosis is a common pathologic consequence of a wide variety of chronic liver diseases, including hepatitis B and C virus infections, alcoholic liver disease and nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis (NAFLD/NASH), and results from an accumulation of extracellular matrix (ECM) following the activation and proliferation of hepatic stellate cells (HSCs). Activated HSCs can contribute to the regression of fibrosis via the release of ECM-degrading proteases. Parenchymal injury and the resulting inflammatory reaction generate a large panel of signals that induce the release of specific transcription factors and morphogens by quiescent HSCs; this release activates the cells and gives them fibrogenic and proinflammatory properties [3]. The HSCs’ exposure to multiple insults and/or inflammatory cytokines (such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α, and interleukin (IL)-1) prompts a transition from a quiescent state to an activated state
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