Role of interleukins in the pathogenesis of cholangiocarcinoma: A literature review

Table 1 Summary of pathophysiological aspects of interleukin-6, interleukin-8 and interleukin-17 in cholangiocarcinoma

Interleukins	Pathogenesis in cholangiocarcinoma
IL-6	IL-6, IL-6R, CRP, gp130, and JAK2 were inversely correlated with vascular invasion, which is a risk factor for poor prognosis in patients with CCA
	Plays a central role in tumorigenesis, angiogenesis, proliferation, and metastasis in biliary tract cancer
	Recently, IL-6 has been shown to induce PD-L1 expression through the mTOR pathway in iCCA
	The inflammatory cytokine such as IL-6 enhances tumor growth in cholangiocarcinoma by altered gene expression via autocrine mechanisms. IL-6 can regulate the activity of DNA methyltransferases, and aberrant DNA methylation can contribute to carcinogenesis
	Chronic inflammation may be a contributing factor in the development of cholangiocarcinomas since inflammation may provide survival signals to the lesion. It demonstrated the autocrine contribution of the inflammatory cytokine-like IL-6 to survival signals and the significant role played by myeloid cell leukaemia-1, an antiapoptotic member of the B-cell leukemia-2 family, in the tumor necrosis factor-related apoptosis-inducing ligand resistance in this neoplasm
IL-8	EMT-associated gene expression was significantly suppressed, and CD97 RNA interference reduced the IL-8-induced stimulation of cell migration and invasion
	When siCXCR2 was used, it was demonstrated to dramatically reduce the carcinogenic effects of IL-8 by preventing the phosphorylation of PI3K/AKT, therefore indicating whether CXCR1 or CXCR2 are downstream effectors of IL-8
	The stimulation of the PI3K pathway of CD97 expression was confirmed by the administration of the inhibitor LY294002
	When CD97 was silenced in nude mice, the substantial effects of IL-8 injection on lung metastasis and tumor development were significantly reduced in vivo
IL-17	IL-17A expression and proliferation were revealed to be significantly correlated in both primary sclerosing cholangitis-CCA and random CCA by correlation analysis. Compared with sporadic CCA cells, PSC-CCA cells exhibit higher tumor cell proliferation
	In vitro, IL-17A promoted the proliferation of CCA cells, which might be a factor in the high rate of proliferation seen in PSC-CCA in situ

IL: Interleukin; CCA: Cholangiocarcinoma; iCCA: Intrahepatic CCA; EMT: Epithelial-mesenchymal transition; CRP: C-reactive protein; gp130: Glycoprotein; JAK2: Janus kinase 2; PD-L1: Programmed death ligand 1; AKT: Protein kinase B; IL-6R: Interleukin 6 receptor. Source: Designed by the authors with the help of articles that are already cited in the references.