Crosstalk network among multiple inflammatory mediators in liver fibrosis

Table 1 Signal pathway-inflammatory mediator crosstalk network in liver fibrosis

Crosstalk family member	Mechanism	Function in liver fibrosis	Biological basis as therapeutic target
TGF-β	Proliferation Migration Collagen production Crosstalk with small compounds Induces NK cell tolerance	Fibrosis activator	Deficiency of TGF-β inhibits liver fibrosis
Wnt/β-catenin	Promotes activation of HSC Collagen I production	Fibrosis activator
TLR-2 TLR1/2 TLR2/6	Activates NF-kB pathway Pro-inflammatory cytokines Activates Kupffer cell and IL-10 production	Inducer or suppressor in liver fibrosis
TLR-3	Crosstalk with IL-17A and γδT cell Crosstalk with CCL5	Inducer or suppressor in liver fibrosis	Loss of TLR3 aggravates liver inflammation
TLR-4	Pro-inflammatory cytokine production	Fibrosis activator	Inhibition of TLR4 promotes liver protection
TLR-5	Crosstalk other pathway Regulates metabolism Anti-inflammatory cytokine production	Fibrosis inhibitor	Activation of TLR5 reduces liver fibrosis
TLR7	Pro-inflammatory cytokine production Activates DCs Crosstalk with IFN signaling pathway	Fibrosis inhibitor
TLR-9	CXCL1 production Neutrophil infiltration	Fibrosis activator
STAT3	Crosstalk with IL-17, IL-10, and IL-6 Crosstalk with other signal pathways	Fibrosis activator or suppressor	Inhibition of STAT3 may inactivate HSCs and prevent liver fibrosis
miR-29b	Crosstalk with PI3K/AKT pathway Crosstalk with TGF-β1/SMAD3 pathway Induces HSC apoptosis	Fibrosis inhibitor
miR-34a-5p	Crosstalk with TGF-β1/SMAD3	Fibrosis inhibitor
miR-130a-3p	Crosstalk with TGFBR1 and TGFBR2 Induces HSC apoptosis	Fibrosis inhibitor
miR-19b	Crosstalk with HSC CCL2	Fibrosis inhibitor
miR-21	Crosstalk with NLRP3 inflammasome/IL-1β axis	Fibrosis regulator
miR-17-5p	Crosstalk with Wnt/β-catenin Activation of HSCs	Fibrosis promoter
miR-142-3p	Crosstalk with TGF-β	Fibrosis inhibitor
miR-200c	Crosstalk with PI3K/Akt	Fibrosis promoter
miR-181b-3p	Crosstalk with TLR4 Kupffer cells	Fibrosis regulator
miR-193a/b-3p	Inhibits activation of HSCs	Fibrosis regulator
miR-26b-5p	Crosstalk with platelet-derived growth factor receptor-β	Fibrosis inhibition
miR-219	Crosstalk with TGF-βRII	Fibrosis inhibition
miR-145	Crosstalk with Krüppel-like factor 4 Promotes activation of HSCs	Fibrosis inhibition

TGF-β: Transforming growth factor-β; TLR: Toll-like receptor; NF-кB: Nuclear factor-кB; HSC: Hepatic stellate cell; DCs: Dendritic cells; NK: Natural killer; IL: Interleukin.