Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis.

Recent studies disclosed that autophagy is induced during and facilitates the process of senescence. Given that biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show senescent features, we examined an involvement of autophagy in the process of biliary epithelial senescence in PBC. We examined immunohistochemically the expression of microtubule-associated proteins-light chain 3beta (LC3), a marker of autophagy, in livers taken from the patients with PBC (n=37) and control livers (n=75). We also examined the co-localization of LC3 with autophagy-related cathepsin D, lysosome-associated membrane protein-1 (LAMP-1), and senescent markers, p16(INK4a) and p21(WAF1/Cip1). We examined the effect of autophagy inhibitor (3-methyladenine) on the induction of cellular senescence and senescence-associated secretion (CCL2 and CX3CL1) in cultured murine BECs. The expression of LC3 was specifically seen in vesicles in BECs in the inflamed and damaged small bile ducts in PBC, when compared with non-inflamed small bile ducts in PBC and in control livers (P<0.01). The expression of LC3 was closely related to the expression of cathepsin D, LAMP-1, and senescent markers. In cultured BECs, oxidative stress, DNA damage, and serum deprivation induced cellular senescence, when compared with control and the inhibition of autophagy significantly decreased the stress-induced cellular senescence (P<0.01). Furthermore, the secretion level of CCL2 and CX3CL1 increased significantly by various stress and suppressed by the inhibition of autophagy (P<0.01). In conclusion, autophagy is specifically seen in the damaged small bile ducts along with cellular senescence in PBC. The inhibition of autophagy suppressed cellular senescence in cultured cells. These findings suggest that autophagy may mediate the process of biliary epithelial senescence and involve in the pathogenesis of bile duct lesions in PBC.