Interleukins in chronic liver disease: lessons learned from experimental mouse models

Figures & data

Table 1 Role of interleukins in experimental mouse models of chronic liver diseases (selection)

Interleukin	Experimental mouse model	Producing cell type	Responding cell type	Effector function	Reference(s)
Pathogenic functions of interleukins
IL-6	HCC	KCs	Hepatocytes	Increased IL-6 production in males leads to increased HCC development	^Citation14,Citation15
				Obesity-induced upregulation of IL-6 promotes HCC	^Citation16
IL-12	Schistosoma mansoni/Toxoplasma gondii double infection			IL-12 downregulates anti-Schistosoma Th2 response, leading to earlier death due to S. mansoni infection	^Citation36
	Malaria		CTLs	IL-12 activates CTLs that kill infected hepatocytes	^Citation34
IL-13	S. mansoni infection	Th2		IL-13 induces production of collagen, α-SMA	^Citation39^–^Citation41
IL-17	PBC	Th17		High levels of IL-17 and Th17 cells increase liver inflammation	^Citation44
	NAFLD	Th17	Hepatocytes	IL-17 increases steatosis in hepatocytes	^Citation48
	Fibrosis	Th17	KCs, HSCs	IL-17 activates HSCs and induces collagen production	^Citation46
	HCC	γδ T cells	MDSCs	IL-17 induces recruitment of MDSCs, which inhibit CTL responses	^Citation49
IL-22	HCC	Infiltrating cells		IL-22-deficiency reduces HCC development	^Citation58
IL-33	CCl4-induced fibrosis	LSECs, HSCs	Th2, ILCs	IL-33 induces IL-13 production in Th2 and ILCs	^Citation62,Citation63
Protective functions of interleukins
IL-6	CCl4-induced fibrosis		NPCs	Abrogation of IL-6 signaling in NPCs enhances fibrosis	^Citation6
				Deletion of IL-6 increases hepatocyte injury and apoptosis	^Citation18
IL-10	Fibrosis	HSCs, LSECs, KCs, lymphocytes	HSCs	IL-10 inhibits HSC activation	^Citation26,Citation27
	Trichinella spiralis infection	Th cells		IL-10 dampens the cytokine response to T. spiralis	^Citation32
IL-12	S. mansoni infection		Th1	IL-12 shifts the immune response towards Th1 (reduced granuloma formation)	^Citation35
IL-22	ASH, NASH			IL-22 reduces fat accumulation and steatosis	^Citation54,Citation55
	Fibrosis		HSCs	IL-22 induces senescence in HSCs	^Citation56

Abbreviations: SMA, smooth-muscle actin; ASH, alcohol-induced steatohepatitis; CCl₄, carbon tetrachloride; CTLs, cytotoxic T lymphocytes; HCC, hepatocellular carcinoma; HSCs, hepatic stellate cells; ILCs, innate lymphoid cells; KCs, Kupffer cells; LSECs, liver sinusoidal endothelial cells; MDSCs, myeloid-derived suppressor cells; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NPCs, nonparenchymal cells; PBC, primary biliary cirrhosis; Th, T helper.

Figure 1 The IL-6 cytokine family and IL6 signaling in the liver.

Notes: (A) Selected members of the IL-6 cytokine family and their receptors (schematic). (B) IL-6 binds to IL-6R/gp80, eg, on hepatocytes. IL-6-gp80 then complexes with the signal-transducing molecule gp130. The complex of IL-6, gp80 (IL-6R), and two gp130 molecules mediates IL-6 signaling via phosphorylation of tyrosine (Y) residues of the intracellular gp130 molecule. Depending on the location of the phosphorylated tyrosines, STAT proteins (mainly STAT3), and also the Ras/MAPK pathway become activated and trigger the downstream effects.
Abbreviation: R, receptor.

Figure 2 Role of interleukins in development of liver fibrosis.

Notes: Interleukins are important immunologic mediators that critically regulate immune responses. During liver fibrogenesis, these cytokines can have profibrotic as well as antifibrotic functions. Typical profibrotic cytokines include IL-13 and IL-17, which directly mediate activation of hepatic stellate cells (HSCs), but also IL-33 and IL-5, which induce IL-13 production in lymphocytes and eosinophilic granulocytes, respectively. IL-10 and IL-22 have been associated with protection from hepatofibrogenesis, as they can prevent activation of HSCs and production of collagen. Furthermore, IL-12 also reduces fibrogenesis through downregulation of profibrotic Th-2 responses.
Abbreviations: Eo, eosinophilic granulocyte; hepa, hepatocyte; ILC, innate lymphoid cell; KC, Kupffer cell; LSEC, liver sinusoidal endothelial cell; MFB, myofibroblast; TC, T cell; Th, T helper.

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