Mediators of Inflammation

Review Article

Therapeutic Potential of IL-17-Mediated Signaling Pathway in Autoimmune Liver Diseases

Table 1

Pathophysiological findings on IL-17 pathway in the development of AILD.


Disease type	Sources	Main findings	References

AIH	Patients	Elevated levels of IL-17 and IL-23 in serum. Increased Th17 cells in peripheral blood	[53, 54]
		Infiltration of Th17 cells with enhanced ROR-γt expression in liver	[53]
		Increased expression of IL-17-related cytokines (IL-23, IL-21, IL-1β, and IL-6) in liver	[53]
		Impairment of CD39^posTregs to suppress IL-17 pathway	[55]
		Greater proportions of IL-17⁺ and RORγ⁺ cells in ngTregs	[56]
	Mouse models	Elevated IL-17 levels in liver and serum	[54]
	Mouse models	Blockade of IL-17 attenuate inflammatory liver injury	[54]

PBC	Patients	Elevated levels of IL-17-related cytokines (IL-17, IL-23, IL-1β, and IL-6) and enhanced gene expression of IL-17-mediated signalling pathway (IL-23 p19, IL-23R, and IL-17) in serum	[57, 58]
		Expansion of Th17 cells with enhanced ROR-γt expression in peripheral blood	[57]
		Aggregation of Th17 cells around interlobular bile ducts	[59–61]
		Enhanced expression of Th17-related cytokines and their cognate receptors (IL-23p19, IL-23p40, IL-17, and IL-23R) in liver	[61]
		Induction of inflammatory cytokines and chemokines (IL-6, IL-1β, IL-23p19, CXCL1, CXCL2, CXCL3, CXCL6, CXCL8, CCL2, and CCL20) by IL-17 in human BECs	[60]
		Upregulation of MIP-3α in human BECs for further recruit of LCs	[62]
	Mouse models
	IL-12Rα−/− mice	Increased frequencies of IL-17 producing cells in liver	[63]
	IL-12Rα−/− mice	Induction of IL-17 responses by splenic CD4⁺ T cells cocultured with NPCs	[59]
	2OA-BSA-immunized mice	Reduction of biliary damage in IL-17A−/− mice and IL-22−/− mice. Lower levels of AMA in IL-17A−/− mice	[64]
	dnTGFβRII mice	Lower titres of anti-gp210 antibodies in mice with deletions of IL-17-related cytokines (IL-12p40, IL-23p19, IL-17, IL-6, and TNF-α)	[65]

PSC	Patients	Infiltration of IL-17⁺ lymphocytes around damaged bile ducts and in areas of neoductular proliferation	[66]
		Increased frequencies of Th17 cells by stimulation of pathogen in peripheral blood	[67]
		Induction of Th17 cells by the selective stimulation of TLR 5 and TLR 7	[66]
	Mouse models (BDL)	Elevated levels of IL-17A in serum	[68]
		Increased gene levels of IL-17-related cytokines and receptors (IL-17 A, IL-17F, IL-17RA, and IL-17RC) in liver	[68]
		Reduction of BDL-induced liver fibrosis in IL-17RA−/− mice	[68]
		Strong expression of IL-17-related cytokines and their receptors in liver resident cells (Kupffer cells, HSC)	[68, 69]
		Induction of TNF-α and TGF-β in Kupffer cells by IL-17 and in turn promotion of IL-17 expressing cells differentiation	[68, 69]

AIH: autoimmune hepatitis; PBC: primary biliary cirrhosis; BEC: biliary epithelial cells; MIP-3α: macrophage inflammatory protein-3α; LC: Langerhans cells; NPCs: nonparenchymal cells; AMA: anti-mitochondrial antibodies; dnTGFβRII: dominant-negative TGF-β receptor II; PSC: primary sclerosing cholangitis; TLR: Toll-like receptor; BDL: bile duct ligation; HSC; hepatic stellate cells; 2OA: 2-octynoic acid.