Interleukin-17 mediates liver progenitor cell transformation into cancer stem cells through downregulation of miR-122

Objective:Cancer stem cells(CSCs)have been the focus of several studies because oftheir involvement in cancer initiation and progression.CSCs were identified in 28%to 50%of hepatocellular carcinomas(HCCs).The origin of CSCs is still unclear,but it has been recently suggested that CSCs could originate from the transformation of liver progenitor cells(LPCs)during chronic liver inflammation.

Novel insights into the impact of liver inflammatory responses on primary liver cancer development

Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context.This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process(initiation steps)and the impact of the immune response favoring tumor cell expansion(progression steps).Several cytokines,namely interleukin(IL)-6,IL-17,IL-1beta,and tumor necrosis factor-alpha,have been described to play a prominent role in the initiation of liver cancers.Additionally,inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response,angiogenesis,and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation.These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation.These strategies are based on the use of anti-inflammatory agents,antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors,metastasis key factors,and microRNAs involved in tumor development.This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.

Th17 cells and their associated cytokines in liver diseases

T helper 17(Th17)cells are a newly identified subset of T helper cells that play important roles in host defense against extracellular bacteria as well as in the pathogenesis of autoimmune disease.The functions of Th17 cells are mediated via the production of several cytokines including interleukin(IL)-17 and IL-22.Recent studies show that the frequency of IL-171 cells is significantly elevated in a variety of chronic liver diseases including alcoholic liver disease,viral hepatitis and hepatocellular carcinoma.IL-17 receptor is expressed virtually on all types of liver cells,while IL-22 receptor expression is restricted to epithelial cells including hepatocytes in the liver.IL-17 seems to play an important role in inducing liver inflammation via stimulating multiple types of liver nonparenchymal cells to produce proinflammatory cytokines and chemokines,while IL-22 appears to be an important factor in promoting hepatocyte survival and proliferation.

Immunopathobiology and therapeutic targets related to cytokines in liver diseases

Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma.The progression of liver disease is controlled by a variety of factors,including liver injury,inflammatory cells,inflammatory mediators,cytokines,and the gut microbiome.In the current review,we discuss recent data on a large number of cytokines that play important roles in regulating liver injury,inflammation,fibrosis,and regeneration,with a focus on interferons and T helper(Th)1,Th2,Th9,Th17,interleukin(IL)-1 family,IL-6 family,and IL-20 family cytokines.Hepatocytes can also produce certain cytokines(such as IL-7,IL-11;and IL-33),and the functions of these cytokines in the liver are briefly summarized.Several cytokines have great therapeutic potential,and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases,which are also described.

Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners

Kupffer cells(KCs),which are liver-resident macrophages,originate from the fetal yolk sac and represent one of the largest macrophage populations in the body.However,the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial.Here,we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy(PHx)and uncover the underlying mechanisms.By using several strains of genetically modified mice and performing immunohistochemical analyses,we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx.Peak KC proliferation was impaired in Il6-knockout(KO)mice and restored after the administration of IL-6 protein,whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice.The source of IL-6 was identified using hepatocyte-and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx.Moreover,peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx,suggesting that IL-6 signaling directly promotes KC proliferation.Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1(SIRT1)contributed to IL-6-mediated KC proliferation in vitro.Genetic deletion of the Sirt1 gene in myeloid cells,including KCs,impaired KC proliferation after PHx.In conclusion,our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation,which is dependent on IL-6 and SIRT1 activation in KCs.