Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is an autoimmune chronic liver disease with worldwide increasing morbidity. However, the etiology of PBC is still unclear. Recently, the epithelial-mesenchymal transition (EMT) and interleukin-17A (IL-17A), a pro-inflammatory cytokine, were proposed to be involved in the pathogenesis of PBC. Therefore, in this study, we aimed to clarify the roles of IL-17A and/or EMT in the onset of PBC. The results showed that the median serum IL-17A level was significantly higher in 29 PBC patients (average course of 40.69 months) than that of 11 healthy controls. The intrahepatic biliary epithelial cells (IBECs), the major target of destruction in PBC, underwent EMT in PBC patients. The immunohistochemical analysis revealed that the protein levels of IL-17A receptor were increased in IBECs and the IL-17A protein was accumulated around the IBECs in the PBC patients. These results imply that the IL-17A-mediated signaling and EMT of intrahepatic biliary epithelial cells (IBEC-EMT) are key pathogenic processes of PBC. To study the association between IL-17A and IBECs-EMT, we then examined if IL-17A induced EMT using a human cell line of IBECs (HIBECs). After the treatment with IL-17A for 48 h, HIBECs changed into bipolar cells with a fibroblastic morphology. Additionally, the results of real-time PCR and Western blot analyses demonstrated that IL-17A up-regulated the expression of a mesenchymal marker vimentin and downregulated the expression of an epithelial marker E-cadherin in HIBECs in the dose-and time-dependent manners. These results suggest that IL-17A may play an important role in the IBECs-EMT.

The Pathogenesis of Primary Biliary Cholangitis: A Comprehensive Review

“…51,67,68 In addition, increased apoptosis has been demonstrated in BECs of PBC patients compared with other chronic cholestatic diseases with similar degree of inflammation. 51,67,69,70 Cholangiocytes in PBC are further characterized by dedifferentiation, linked to decreased expression of biliary 71 and epithelial markers, acquisition of proinflammatory, profibrotic and mesenchymal markers, 72 and deregulated autophagy followed by cellular senescence in BECs. 73,74 Finally, necroptosis, a necrotic cell death pathway, 75 and autophagy 76 have also been suggested as key players in PBC pathogenesis.…”

Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis

“…The subtype 17 of T helper lymphocyte cells is increased in almost all chronic and fibrosing liver diseases, including ALD, such as autoimmune hepatitis (AIH) ( 50 , 110 , 111 ), primary sclerosing cholangitis (PSC) ( 112 , 113 ), PBC ( 16 , 83 , 114 , 115 ); biliary atresia ( 29 , 81 , 116 ), non-alcoholic steatohepatitis ( 85 , 117 , 118 ), and viral hepatitis ( 42 , 44 , 58 , 109 ). These findings reveal the pivotal role of the Th17/IL-17 axis in liver fibrogenesis.…”

“…There are receptors for IL-17 expressed in hepatocytes, in the liver sinusoids endothelial cells, in hepatic stellate cells (HSCs), and Kupffer cells (KC) ( 13 ). The functional implication of IL-17 in liver tissue is well characterized in the activation and/or stimulation of HSCs and KC ( 13 , 17 , 127 ) and cholangiocytes ( 115 , 116 ).…”

MicroRNA‐506 promotes primary biliary cholangitis–like features in cholangiocytes and immune activation

“…In the current report, the evaluation of different lengths of miR‐506 promoter indicates that the full‐length ∼3‐kb region of miR‐506 promoter is required for its stimulation by proinflammatory cytokines found overexpressed in PBC livers such as IL8, IL12, IL17, IL18, and TNFα. These proinflammatory cytokines are involved in PBC immune response modulation and are associated with disease progression . Thus, in PBC patients, the cytokine profile in serum and liver samples suggests activation and liver recruitment of T helper 1 (Th1) and Th17 cells .…”

“…These proinflammatory cytokines are involved in PBC immune response modulation and are associated with disease progression. (18,(29)(30)(31)(32) Thus, in PBC patients, the cytokine profile in serum and liver samples suggests activation and liver recruitment of T helper 1 (Th1) and Th17 cells. (30) lL12 and IL23, which are produced by antigen presenting cells, are responsible for promoting Th1 and Th17 immune responses, respectively.…”