Abstract
Accumulating studies suggest that senescent biliary epithelial cells (BECs) produce senescence-associated secretory phenotypes (SASPs) and play various roles in the pathogenesis of primary biliary cholangitis (PBC) and other cholangiopathies. We examined comprehensive profiles of senescent BECs and its contribution to the pathogenesis of PBC taking advantage of microarray analysis. cDNA microarray analysis revealed that 1841 genes including CCL2, IFIT3, CPQ were commonly up-regulated in senescent BECs cultured in serum depleted media or media with glycochenodeoxycholic acid. Knockdown of IFIT3 significantly suppressed cellular senescence (p < 0.01) and significantly increased apoptosis (p < 0.01) in BECs treated with serum depletion or glycochenodeoxycholic acid. Significantly increased expression of IFIT3 was seen in senescent BECs in small bile ducts showing cholangitis and in ductular reactions in PBC, compared to control livers (p < 0.01). An inadequate response to UDCA was inversely correlated to the increased expression of IFIT3 in small bile duct in PBC (p < 0.05). In conclusion, the expression of various genes related to immunity and inflammation including SASPs were increased in senescent BECs. Upregulated IFIT3 in senescent BECs may be associated with the pathogenesis of PBC and may be a possible therapeutic target in PBC.
Highlights
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterized by a unique chronic non-suppurative destructive cholangitis (CNSDC) in small bile ducts and serum anti-mitochondrial antibodies (AMAs)[1,2,3]
Upregulated genes in senescent biliary epithelial cells (BECs), which show more than twofold change compared to control, were 2870 and 2789 genes in serum depletion and glycochenodeoxycholic acid (GCDC) treatment for 7 days, respectively. 1841 genes were commonly upregulated in both 2 conditions
Major genes commonly upregulated in senescent BECs induced by serum depletion and GCDC treatment included CCL2, IFIT3, CPQ, NUPR1 and CIB2 (Table 1, Supplementary table S1)
Summary
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterized by a unique chronic non-suppurative destructive cholangitis (CNSDC) in small bile ducts and serum anti-mitochondrial antibodies (AMAs)[1,2,3]. Exact mechanisms inducing cellular senescence in PBC remains unknown, so far, cellular senescence can be induced by treatments with oxidative stress, serum depletion or glycochenodeoxycholic acid (GCDC) in cultured BECs in our previous studies[5,8,12,15]. It is conceivable that senescent BECs may participate in the pathogenesis of PBC and other various cholangiopathies by secreting senescence-associated secretory phenotypes (SASPs), such as augmented inflammation, progression of fibrosis and bile duct loss[8,9,13,14,15,16]. Results of cDNA microarray analysis showed that some of the commonly up-regulated genes in senescent BECs following in vitro incubation in serum depleted media or treatment with GCDC included CCL2, IFIT3 CPQ. A participation of IFN pathways in the pathogenesis of PBC was previously r eported[20,21,22,23,24], so we selected IFIT3 for further examination
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