Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease

Table 7 Studies and their findings on interleukin-1α, interleukin-1β, interleukin-1Ra and interleukin-18

Cytokines	Finding	Ref.
IL-1α	Acute treatment of 3T3-L1 adipocytes with IL-1α led to transient IR at IRS-1 level, mediated by its serine phosphorylation	[254]
IL-1β
Human	Weight loss in severely obese patients led to decreased IL-1β in subcutaneous adipose tissue and in liver without effect on adipose IL-1α IL-1β was significantly higher in subcutaneous/visceral adipose tissue than in liver	[253]
	IL1-β genetic variants in Japanese population associated with NASH	[259]
Animal	Hepatic IL-1α and IL-1β increased in NASH animal models Mice deficient in either cytokine not prone to NASH and fibrosis development	[255]
	In experimental models TLR2 and palmitic acid activated inflammasome in Kupffer cells and produced IL-1α and IL-1β	[257]
	IL-1β/ApoE-deficient mice had less pronounced atherosclerosis	[262]
	Treatment with an IL-1β antibody improved glycemic control and β cell function in diet-induced obese mice	[263]
	Animal NASH model showed increased macrophage infiltration in adipose tissue as well as in liver accompanied with increased expression of IL-1β	[264]
	Hepatic steatosis partially mediated by Kupffer cells that produced IL-1β which suppressed PPAR-α	[266]
	In diet induced NASH mice probiotics decreased hepatic IL-1β mRNA	[268]
In vitro	IL-1β inhibited insulin-induced phosphorylation of the insulin receptor beta subunit, IRS1, protein kinase B and extracellular regulated kinase 1/2 in murine and human adipocytes that lead to IR and inhibition of lipogenesis IL-1β decreased adiponectin	[260]
	IL-1β promoted hepatic fibrosis by upregulating TIMMP-1 in rat HSC mediated by p38 mitogen-activated protein kinases and JNK	[267]
IL-1Ra	IL-1Ra decreased glucose uptake in muscle and was upregulated in WAT of diet-induce obese mice	[270]
	Atherogenic diet in IL-1Ra deficient mice caused severe liver steatosis, inflammation and portal fibrosis	[272]
IL-18	In obese women IL-18 positively correlated with body weight and visceral fat	[275]
	In T2DM patients and non-diabetic controls IL-18 plasma levels positively correlated with HOMA-IR	[276]
	In male patients with NAFLD, IL-18 alone in the absence of metabolic risks cannot contribute to evolution of NAFLD	[278]
	IL-18 enhanced cytokine production by stimulating TNF-α synthesis in immune cells	[279]
	Il-18 administrated with IL-12 induced mouse fatty liver in an IFN-γ dependent manner	[280]
	Rosiglitazone in NAFLD rat model reduced IL-18 and caspase-1 in liver as well as improved histology	[277]

IL-1α: Interleukin 1 alfa; IR: Insulin resistance; IRS-1: Insulin receptor substrate 1; IL-1β: Interleukin 1 beta; IL-18: Interleukin 18; NASH: Nonalcoholic steatohepatitis; TLR2: Toll-like receptor 2; PPAR-α: Peroxisome proliferator-activated receptor alfa; TIMMP-1: Tissue inhibitor of matrix metalloproteinase-1; HSC: Hepatic stellate cells; JNK: c-Jun N-terminal kinases; WAT: White adipose tissue; T2DM: Type 2 diabetes mellitus; HOMA-IR: Homeostasis model assessment-estimated insulin resistance; NAFLD: Non-alcoholic fatty liver disease; TNF-α: Tumor necrosis factor alpha; IL-12: Interleukin 12; IFNγ: Interferon gamma.