52 There appears to be a paracrine loop operative in which IL-6 potently down-regulates NTPD2 on PFs (without altering PF myofibroblastic differentiation); NTPD2 in turn regulates G protein–coupled P2Y receptors for extracellular adenosine triphosphate and other nucleotides, which mediate BDE proliferation.53

Additionally, non-HSC rat liver myofibroblasts express IL-6, providing a mechanism for autocrine regulation as well.54 The result is that loss of NTPD2, which is observed in biliary cirrhosis in rats and humans, leads to BDE hyperproliferation.55, 56 To complete the loop, IL-6 is released by BDE in response to extracellular adenosine triphosphate, providing a feed-forward mechanism for the continued production of IL-6 and the perpetuation of bile ductular proliferation.52 MCP-1 was first identified as a regulator of monocyte/macrophage chemotaxis,57 and may

Ceritinib clinical trial be important as a regulator of PF myofibroblastic differentiation and fibrogenesis. BDE express MCP-1 messenger RNA and are the liver cells expressing MCP-1 messenger RNA most strongly in chronic hepatitis.58 There is now direct evidence that BDE signal to PFs through MCP-1 release. MCP-1 up-regulates PF proliferation, myofibroblastic differentiation, and procollagen-1 messenger RNA expression and down-regulates NTPD2 expression. Furthermore, conditioned medium from BDE STA-9090 datasheet isolated from BDL-treated rats induced PF myofibroblastic differentiation, which was inhibited by an MCP-1 blocking antibody.59 The identity of the MCP-1

receptor expressed by PFs is not known. These cells fail to express the MCP-1 cognate receptor chemokine (C-C motif) receptor 2, although chemokine (C-C motif) receptor 2 null mice are protected from BDL-induced cirrhosis.59, 60 HSCs, initially studied almost exclusively as matrix-producing cells, are now known to have many complex functions.61 Although our understanding of PF-mediated fibrogenesis is still in its infancy, two additional points warrant mention. PFs appear to be the major elastin-expressing cells (aside from vascular smooth muscle cells) in the liver, and some investigators have shown that elastin deposition increases as PFs 上海皓元 proliferate and fibrosis progresses.35, 36 Although not all groups agree that elastin is specific for PFs (as opposed to HSCs),62 the data raise interesting points beyond the use of elastin as a marker for PFs. Elastic fibers, which are formed from fibrillin microfibrils, with or without a core of elastin, are important determinants of the mechanical properties of tissues, providing resilience, in contrast to the fibrillar collagens (typical of the liver scar) which provide rigidity. Fibrillin is expressed by both HSCs and PFs36, 63; thus, the elastic fibers around HSCs and PFs are structurally different.