Interferon-γ down-regulates expression of tumor necrosis factor-α converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats

Abstract

Abstract. Interferon-Á (IFN-Á) is a potent cytokine that exerts antiproliferative and antifibrogenic effects on hepatic stellate cells (HSCs). Although therapeutic application of IFN-Á for chronic liver diseases is anticipated, the responses of activated HSCs to IFN-Á have not been fully elucidated. To seek unknown molecules and pathways that might be responsive to IFN-Á treatment in activated HSCs, we examined global protein expression profiles using two-dimensional gel electrophoresis combined with peptide mass fingerprint. We identified 76 increased and 59 decreased spots (>3-fold increase or decrease, total 135 spots). Database analysis suggested that the following four pathways were involved in alteration of HSCs toward a quiescent phenotype in response to IFN-Á: i) down-regulation of the TGF-ß and PDGF signaling pathways; ii) reorganization of intermediate filaments; iii) up-regulation of fatty acid metabolism; iv) decreased expression of TNF-· converting enzyme (TACE)/a disintegrin and metalloproteinase 17 (ADAM17), which is responsible for shedding of the proinflammatory cytokine TNF-·. We confirmed down-regulation of both ADAM17 expression and soluble TNF-· secretion by Western blotting and real-time PCR. TNF-· mRNA/protein expression was not altered by IFN-Á treatment. Our data suggest that IFN-Á stimulation suppresses the activated phenotype of HSCs in vitro through multiple pathways. Of these pathways, down-regulation of ADAM17 expression may play a role in blocking the auto-activation mechanism of cultured HSCs through activation of the TNF-· signaling and shedding pathways.

CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver

“…According to the literature, we thought to evaluate the involvement of the two putative sheddases ADAM10 and ADAM17 that were highly expressed in our cells. Although the IFN-γ-dependent down-regulation of ADAM17 in rat HSC was recently reported by using a differential proteomic assay [19], the expression levels of ADAM10 and ADAM17 were not modified by IFN-γ treatment in human cultured HSC. Surprisingly, the specific inhibitor hydroxamate GW280264X that blocks ADAM10 as well as ADAM17 [15] partially affected the cleavage of CX3CL1 that was totally inhibited by batimastat suggesting the implication of another metalloprotease.…”

“…As main source of matrix and proteases, the role of the profibrogenic hepatic stellate cells (HSCs) in this process has been well documented [17]. More recently, increased expression of members of ADAM family, including ADAM9, ADAM12 and ADAM17 was reported in patients with chronic liver diseases and expressed by the activated HSC [18][19][20][21]. In the present study, we investigated whether HSCs are involved in CX3CL1 shedding during liver injury.…”

Interferon-γ-mediated Inhibition of Serum Response Factor-dependent Smooth Muscle-specific Gene Expression

“…In the context of IFN␥ biology, our work is consistent with previous studies emphasizing a number of IFN␥-regulated genes. Further, elucidation of such targets is critical for understanding IFN␥-mediated biological effects (1,3,29).…”

Angiotensin II and epidermal growth factor receptor cross‐talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines

“…42 We have previously demonstrated that interferon-g treatment induces HSCs to downregulate ADAM17/TACE expression in association with phenotypic transformation and decreased secretion of TNFa, which is a representative cytokine that activates HSCs. 43 In addition, Mazzoca et al 31 have shown that ADAM9-S secreted from activated HSCs promotes the invasion of metastatic liver cancers. Locally elevated levels of AngII in HCC and background tissues (liver fibrosis) may affect stromal-tumor cell (HSC-HCC) interdependence, and contribute to tumor progression and liver dysfunction in patients with HCC.…”