Abstract
ERα, one of the classical receptors of estrogen, has been found to be abnormally up-regulated in patients with primary biliary cholangitis (PBC), which is an important factor leading to ductopenia. ERα-mediated signaling pathways are involved in proliferation of human intrahepatic biliary epithelial cells (HiBECs) and portal inflammation. Our previous studies have shown that the expression levels of ERα in the liver tissues of PBC patients are positively correlated with the levels of serum pro-inflammatory cytokines. The present study was designed to assess the relationship between abnormal ERα expression in small bile ducts and the progression of PBC. We examined the levels of multiple cytokines and analyzed their relationship with clinical parameters of livers functions in a cohort of 43 PBC patients and 45 healthy controls (HC). The levels of ERα expression and the relation with the levels of cytokines were further assessed. The localization of cytokines and ERα-mediated signaling pathways in liver were examined using immunohistochemistry. The possible underlying mechanisms of these alterations in PBC were explored in vitro. Our results demonstrated that the levels of IL-6, IL-8, and TNF-α were increased in PBC patients, and positively correlated with the serum AKP levels and ERα expression levels. Moreover, the expression of these cytokines were up-regulated in HiBECs that were stimulated with 17β-estradiol and PPT (an ERα agonist) and they also were positive in intrahepatic bile duct of PBC patients. The ERα-mediated expression of pro-inflammatory cytokines was induced by JNK, P38, and STAT3 phosphorylation in HiBECs. In addition, the CD54 expression was increased in HiBECs after ERα activation, which induced peripheral blood monouclear cells (PBMCs) recruitment. In conclusion, the present study highlighted a key role of abnormal ERα expression in inducing an inflammatory phenotype of HiBECs, which was critical in the development of inflammation and damage in small bile duct.
Highlights
Primary biliary cholangitis (PBC) is an occult and chronic progressive autoimmune liver disease, and, if untreated, will culminate into end-stage biliary cirrhosis, leading to liver failure [1]
Tsuneyama et al have reviewed the types of immune cells which infiltrate into the peripheral of small bile ducts in PBC patients; they have found that T cells comprise 55% of the cellular infiltrate, macrophages and B cells/plasma cells account for ∼30 and 10% in early stage, respectively, showing chronic non-suppurative destructive cholangitis (CNSDC), and these activated immune cells play important roles in initiating the breakdown of tolerance [6]
The results showed that the estrogen receptor α (ERα) expression levels were up-regulated in human intrahepatic biliary epithelial cells (HiBECs) that were treated with 17β-estradiol and PPT (Figures 4G,H), and fulvestrant showed an inhibitory effect on ERα expression (Figures 4G,H)
Summary
Primary biliary cholangitis (PBC) is an occult and chronic progressive autoimmune liver disease, and, if untreated, will culminate into end-stage biliary cirrhosis, leading to liver failure [1]. Some scholars believe that the pathological starting point of PBC is autoimmune-mediated injury of small bile duct, and the immunological interaction between human intrahepatic biliary epithelial cells (HiBECs) and surrounding inflammatory cells is a pivotal mechanism to trigger small bile duct lesions [7]. Cholangiocytes in small bile duct of PBC patients are expressing various cytokines and chemokines in order to generate and sustain the specific surrounding inflammatory conditions, which will induce HiBECs apoptosis and exacerbate bile duct injury [6]. HiBECs in damaged biliary duct will have up-regulated expression of phagocytosis related receptor phosphatidylserine receptor (PSR), which is involved in phagocytosis of adjacent injured and apoptotic peers due to immunological interaction [10]. There is no clear mechanism to explain the causes of the onset abnormal activation of HiBECs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
