The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis†

Abstract

The hepatic wound-healing response to chronic noxious stimuli may lead to liver fibrosis, a condition characterized by excessive deposition of extracellular matrix. Fibrogenic cells, including hepatic stellate cells and myofibroblasts, are activated in response to a variety of cytokines, growth factors, and inflammatory mediators. The involvement of members of the epidermal growth factor family in this process has been suggested. Amphiregulin (AR) is an epidermal growth factor receptor (EGFR) ligand specifically induced upon liver injury. Here, we have addressed the in vivo role of AR in experimental liver fibrosis. To this end, liver fibrosis was induced in AR؉/؉ and AR؊/؊ mice by chronic CCl 4 administration. Histological and molecular markers of hepatic fibrogenesis were measured. Additionally, the response of cultured human and mouse liver fibrogenic cells to AR was evaluated. We observed that AR was expressed in isolated Kupffer cells and liver fibrogenic cells in response to inflamatory stimuli and platelet-derived growth factor, respectively. We demonstrate that the expression of ␣-smooth muscle actin and collagen deposition were markedly reduced in AR؊/؊ mice compared to AR؉/؉ animals. AR؊/؊ mice also showed reduced expression of tissue inhibitor of metalloproteinases-1 and connective tissue growth factor, two genes that responded to AR treatment in cultured fibrogenic cells. AR also stimulated cell proliferation and exerted a potent antiapoptotic effect on isolated fibrogenic cells. Conclusion: These results indicate that among the different EGFR ligands, AR plays a specific role in liver fibrosis. AR may contribute to the expression of fibrogenic mediators, as well as to the growth and survival of fibrogenic cells. Additionally, our data lend further support to the role of the EGFR system in hepatic fibrogenesis. ( Pio XII, n55, 31008 Pamplona, Spain. E-mail: maavila@unav.es (M.A.A.) and cberasain@unav.es (C.B.); fax: 34-948-194717.

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

“…2 It is also known that amphiregulin amplifies the HSC response through increased production of CTGF and TIMP-1. 39 Thus, the inhibition of amphiregulin expression by melatonin in CCl 4 -treated mice supports the suggestion that suppression of the amphiregulin signaling system could be a new target in the prevention of liver fibrosis.…”

“…38 The expression of amphiregulin increases markedly in liver injury induced by CCl 4 , 39 and amphiregulin deficient-mice develop significantly less collagen accumulation. 40 We have previously reported that suppression of amphiregulin signals contributes to the protective effects of quercetin in cirrhotic rats with common bile duct ligation, 7 and in mice fed a methionine-choline-deficient diet.…”

Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

“…Although few studies have been undertaken to define the specific role of AR in the pathogenesis of tissue fibrosis, including pulmonary fibrosis, the available results have been conflicting to date. In an animal model of liver fibrosis, AR expression is significantly induced, and the absence of AR markedly reduced ␣-SMA expression and collagen deposition in the liver, implicating AR contribution in the development or the progression of liver fibrosis (42). In support of this notion, the use of gefitinib, a EGFR blocker, significantly inhibits bleomycin-induced pulmonary fibrosis (22).…”

Metalloproteinases in liver fibrosis: current insights

“…[97][98][99][100][101][102] EGFR is expressed in both the parenchymal and nonparenchymal liver cells, and several studies have reported that amphiregulin enhances liver fibrosis through its mitogenic effect on HSCs. 102,103 These effects, protecting hepatocytes as well as profibrotic HSCs, could account for the fact that ADAM17 hepatocyte-deficient mice do not develop exaggerated fibrosis after intoxication with CCl 4 (our observation, unpublished). Similarly, despite certain dysregulations, no major liver regeneration phenotypes were observed in mice with ADAM17 deficiency in either hepatocytes or Kupffer cells.…”