Figure 3

Hypothesis: fibrogenic signaling induced by Toll-like receptor (TLR)4 in hepatic stellate cells (HSCs) and Kupffer cells (KCs), and the effect of TLR4 single nucleotide polymorphisms (SNPs). HSCs have intact TLR4 signaling. Both pathogen-associated molecular patterns (PAMPs; exogenous ligands, for example, LPS) and damage-associated molecular patterns (DAMPs; endogenous ligands, for example, HMGB1) may activate TLR4 in HSCs, signaling through NF-κB, leading to downregulation of the transmembrane inhibitory TGF-β1 pseudoreceptor bone morphogenic protein and active membrane bound inhibitor (BAMBI) on HSCs, a key fibrogenic cell in liver. As a result, net TGF-β1 activity increases, enhancing extracellular matrix production. Concurrently, TLR4 signaling in HSCs also increases the activity and migration of KCs. Activation of TLR4 signaling on KCs enhances the interaction within KCs and HSCs by activating the production of profibrogenic factors. Polymorphisms of the TLR4 gene, which decrease the recognition of PAMPs and DAMPs by TLR4 on HSCs and KCs, decrease the activation of TLR4 signaling and downstream production of proinflammatory cytokines, chemokines and fibrogenic proteins such as BAMBI. The TLR4 single nucleotide polymorphisms (SNPs) confer an overall protective effect against inflammation and fibrogenesis.