Overall, these findings sustain a prominent role for TNF-α in the pathogenesis of PBC, suggesting that anti-TNF-α treatment, currently used for most inflammatory rheumatic conditions, such as RA, ankylosing

spondylitis (AS), and CD, may also represent a promising agent in PBC. Pathway analysis GSI-IX datasheet of both the Italian and Canadian GWAS PBC cohorts have highlighted the phosphatidylinositol signaling system pathway, which is an integral component of the adaptive immune response and is essential for the maintenance of self-tolerance [41]. Possible involvement of the phosphatidylinositol pathway in PBC appears to fit well with the TNF hypothesis as this signaling system has been shown to mediate the effects of TNF-α on NF-κB activation [72, 73]. The same pathway analysis also identified the hedgehog (Hh) signaling system, suggesting

its involvement in PBC genetic susceptibility. Hh proteins comprise a group of secreted proteins that are involved in organogenesis and have been shown to promote adult stem cell proliferation [74-76]. Hh signaling has been widely described in PBC. It is involved in the ductular response to cholestatic damage in PBC, characterized by periportal accumulation of proliferating bile ductular cells and associated stromal elements, including myofibroblastic cells and fibrous matrix [77]. Hh signaling was found to be increased in a murine model of bile JNK animal study duct ligation in periportal epithelial cells expressing pan-cytokeratin, representing potential liver progenitor cell populations [63]. Hh signaling has also been shown to be able to promote the survival of biliary epithelial cells, possibly mediated through the inhibition of caspase activity [16]. Lastly, Hh signaling pathway activation has

been associated with upregulation of ductular cell expression of genes that promote inflammatory response, such as the gene producing Cxcl16; Hh dependent induction of Cxcl16, demonstrated Y27632 in both bile duct ligated rats and humans with PBC, resulted in Natural Killer T (NKT) cell chemotaxis toward cholangiocytes in vitro [17]. Hh signaling may represent an important protective factor within the damaged liver, promoting the survival of small periportal epithelial cells representing potential hepatic progenitor cells. Despite the preliminary nature of these studies, the Hh signaling pathway may represent a new therapeutic target to protect or promote cell proliferation and tissue repair within the chronically damaged liver in PBC and other chronic liver diseases. Some scientists believe that, as humans did not evolve in an environment of drug therapies, there is no evolutionary pressure on responses to recently developed pharmacologic agents.