Inflammasomes are
protein complexes that produce IL-1β in response to damage or pathogens. As such,
inflammasomes are involved in several types of hepatic
fibrosis. However, the mechanisms by which these complexes drive the liver's fibrogenic status remain unclear. We co-cultured differentiated macrophages (the THP-1 cell line or human monocyte-derived macrophages (MDMs)) with human hepatic fibroblasts (either the LX-2 cell line or primary human hepatic stellate cells (HSCs)). The
inflammasome pathway was activated with
lipopolysaccharide (LPS) and
monosodium urate (MSU) crystals, and the HSCs' responses were analyzed. Our results show that co-culture of HSCs with THP-1 cells upregulated transcription of the genes coding for
metalloproteinase (MMP)-3 and MMP-9. After
inflammasome pathway activation, the HSCs' phenotype was the same in the presence of THP-1 cells or MDMs (i.e. upregulation of
MMP-3,
MMP-9, and the pro-inflammatory
cytokine IL-1β). We found that two
cytokines were involved in these changes: IL-1β regulated MMP-3 and IL-1β
mRNA expression, whereas TNF-α regulated MMP-9
mRNA expression. Experiments with primary cells revealed that a general inflammatory environment is responsible for the downregulation of pro-fibrotic markers. Our present results suggest that
inflammasome pathway activation in macrophages leads to a pro-inflammatory environment for HSCs leading to
MMP/TIMP imbalance and enhanced fibrolytic properties.