Aminoacyl-tRNA synthetase interacting multi-functional protein 1 attenuates liver fibrosis by inhibiting TGFβ signaling

Ahn,Jongchan; Son,Mi  Kwon; Jung,Kyung  Hee; Kim,Kwangil; Kim,Gi  Jin; Lee,Soo-Hong; Hong,Soon-Sun; Park,Sang  Gyu

doi:10.3892/ijo.2015.3303

Aminoacyl-tRNA synthetase interacting multi-functional protein 1 attenuates liver fibrosis by inhibiting TGFβ signaling

Authors:
- Jongchan Ahn
- Mi Kwon Son
- Kyung Hee Jung
- Kwangil Kim
- Gi Jin Kim
- Soo-Hong Lee
- Soon-Sun Hong
- Sang Gyu Park
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Affiliations: Department of Biomedical Science, College of Life Science, CHA University, Gyunggido, Republic of Korea, Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea, Department of Pathology, Bundang CHA General Hospital, CHA University, Gyunggido, Republic of Korea , Department of Pharmacy, College of Pharmacy, Ajou University, Suwon, Gyunggido, Republic of Korea
Published online on: December 18, 2015 https://doi.org/10.3892/ijo.2015.3303
Pages: 747-755

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Abstract

The aminoacyl-tRNA synthetase interacting multi-functional protein 1 (AIMP1) participates in a variety of cellular processes, including translation, cell proliferation, inflammation and wound healing. Previously, we showed that the N-terminal peptide of AIMP1 (6-46 aa) induced ERK phosphorylation. Liver fibrosis is characterized by excessive deposition of extracellular matrix, which is induced by TGFβ signaling, and activated ERK is known to induce the phosphorylation of SMAD, thereby inhibiting TGFβ signaling. We assessed whether the AIMP1 peptide can inhibit collagen synthesis in hepatic stellate cells (HSCs) by activating ERK. The AIMP1 peptide induced phosphorylation of SMAD2 via ERK activation, and inhibited the nuclear translocation of SMAD, resulting in a reduction of the synthesis of type I collagen. The AIMP1 peptide attenuated liver fibrosis induced by CCl4, in a dose-dependent manner. Masson-Trichrome staining showed that the AIMP1 peptide reduced collagen deposition. Immunohistochemical staining showed that the levels of α-SMA, TGFβ and type I collagen were all reduced by the AIMP1 peptide. Liver toxicity analysis showed that the AIMP1 peptide improved the levels of relevant biological parameters in the blood. These results suggest that AIMP1 peptide may have potential for development as a therapeutic agent to treat liver fibrosis.

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1	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
2	Li JT, Liao ZX, Ping J, Xu D and Wang H: Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies. J Gastroenterol. 43:419–428. 2008. View Article : Google Scholar : PubMed/NCBI
3	Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP and Forbes SJ: The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 130:1807–1821. 2006. View Article : Google Scholar : PubMed/NCBI
4	Pinzani M and Rombouts K: Liver fibrosis: From the bench to clinical targets. Dig Liver Dis. 36:231–242. 2004. View Article : Google Scholar : PubMed/NCBI
5	Iredale JP, Benyon RC, Arthur MJ, Ferris WF, Alcolado R, Winwood PJ, Clark N and Murphy G: Tissue inhibitor of metal-loproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology. 24:176–184. 1996. View Article : Google Scholar : PubMed/NCBI
6	Cheng JH, She H, Han YP, Wang J, Xiong S, Asahina K and Tsukamoto H: Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 294:G39–G49. 2008. View Article : Google Scholar
7	Yoshiji H, Noguchi R, Kuriyama S, Ikenaka Y, Yoshii J, Yanase K, Namisaki T, Kitade M, Masaki T and Fukui H: Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol. 288:G907–G913. 2005. View Article : Google Scholar
8	Son MK, Ryu YL, Jung KH, Lee H, Lee HS, Yan HH, Park HJ, Ryu JK, Suh JK, Hong S, et al: HS-173, a novel PI3K inhibitor, attenuates the activation of hepatic stellate cells in liver fibrosis. Sci Rep. 3:34702013. View Article : Google Scholar : PubMed/NCBI
9	Bueno M, Salgado S, Beas-Zárate C and Armendariz-Borunda J: Urokinase-type plasminogen activator gene therapy in liver cirrhosis is mediated by collagens gene expression down-regulation and up-regulation of MMPs, HGF and VEGF. J Gene Med. 8:1291–1299. 2006. View Article : Google Scholar : PubMed/NCBI
10	Anselmi K, Stolz DB, Nalesnik M, Watkins SC, Kamath R and Gandhi CR: Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition. J Hepatol. 47:103–113. 2007. View Article : Google Scholar : PubMed/NCBI
11	Shackel N and Rockey D: In pursuit of the ‘Holy Grail’ - stem cells, hepatic injury, fibrogenesis and repair. Hepatology. 41:16–18. 2005. View Article : Google Scholar : PubMed/NCBI
12	LeRoy EC, Trojanowska MI and Smith EA: Cytokines and human fibrosis. Eur Cytokine Netw. 1:215–219. 1990.PubMed/NCBI
13	Kane CJ, Hebda PA, Mansbridge JN and Hanawalt PC: Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutaneous wound healing. J Cell Physiol. 148:157–173. 1991. View Article : Google Scholar : PubMed/NCBI
14	Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB and Sporn MB: Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA. 84:5788–5792. 1987. View Article : Google Scholar : PubMed/NCBI
15	Funaba M, Zimmerman CM and Mathews LS: Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J Biol Chem. 277:41361–41368. 2002. View Article : Google Scholar : PubMed/NCBI
16	Matsuura I, Wang G, He D and Liu F: Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. Biochemistry. 44:12546–12553. 2005. View Article : Google Scholar : PubMed/NCBI
17	Mulder KM: Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev. 11:23–35. 2000. View Article : Google Scholar : PubMed/NCBI
18	Kretzschmar M, Doody J, Timokhina I and Massagué J: A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev. 13:804–816. 1999. View Article : Google Scholar : PubMed/NCBI
19	Conery AR, Cao Y, Thompson EA, Townsend CM Jr, Ko TC and Luo K: Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol. 6:366–372. 2004. View Article : Google Scholar : PubMed/NCBI
20	Song K, Wang H, Krebs TL and Danielpour D: Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. EMBO J. 25:58–69. 2006. View Article : Google Scholar
21	Remy I, Montmarquette A and Michnick SW: PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol. 6:358–365. 2004. View Article : Google Scholar : PubMed/NCBI
22	Takayama S, Murakami S, Miki Y, Ikezawa K, Tasaka S, Terashima A, Asano T and Okada H: Effects of basic fibroblast growth factor on human periodontal ligament cells. J Periodontal Res. 32:667–675. 1997. View Article : Google Scholar : PubMed/NCBI
23	Silverio-Ruiz KG, Martinez AE, Garlet GP, Barbosa CF, Silva JS, Cicarelli RM, Valentini SR, Abi-Rached RS and Junior CR: Opposite effects of bFGF and TGF-beta on collagen metabolism by human periodontal ligament fibroblasts. Cytokine. 39:130–137. 2007. View Article : Google Scholar : PubMed/NCBI
24	Quevillon S, Agou F, Robinson JC and Mirande M: The p43 component of the mammalian multi-synthetase complex is likely to be the precursor of the endothelial monocyte-activating polypeptide II cytokine. J Biol Chem. 272:32573–32579. 1997. View Article : Google Scholar
25	Matschurat S, Knies UE, Person V, Fink L, Stoelcker B, Ebenebe C, Behrensdorf HA, Schaper J and Clauss M: Regulation of EMAP II by hypoxia. Am J Pathol. 162:93–103. 2003. View Article : Google Scholar : PubMed/NCBI
26	Park SG, Shin H, Shin YK, Lee Y, Choi EC, Park BJ and Kim S: The novel cytokine p43 stimulates dermal fibroblast proliferation and wound repair. Am J Pathol. 166:387–398. 2005. View Article : Google Scholar : PubMed/NCBI
27	Park SG, Kang YS, Kim JY, Lee CS, Ko YG, Lee WJ, Lee KU, Yeom YI and Kim S: Hormonal activity of AIMP1/p43 for glucose homeostasis. Proc Natl Acad Sci USA. 103:14913–14918. 2006. View Article : Google Scholar : PubMed/NCBI
28	Ko YG, Park H, Kim T, Lee JW, Park SG, Seol W, Kim JE, Lee WH, Kim SH, Park JE, et al: A cofactor of tRNA synthetase, p43, is secreted to up-regulate proinflammatory genes. J Biol Chem. 276:23028–23033. 2001. View Article : Google Scholar : PubMed/NCBI
29	Park SG, Kang YS, Ahn YH, Lee SH, Kim KR, Kim KW, Koh GY, Ko YG and Kim S: Dose-dependent biphasic activity of tRNA synthetase-associating factor, p43, in angiogenesis. J Biol Chem. 277:45243–45248. 2002. View Article : Google Scholar : PubMed/NCBI
30	Park H, Park SG, Lee JW, Kim T, Kim G, Ko YG and Kim S: Monocyte cell adhesion induced by a human aminoacyl-tRNA synthetase-associated factor, p43: Identification of the related adhesion molecules and signal pathways. J Leukoc Biol. 71:223–230. 2002.PubMed/NCBI
31	Kim E, Kim SH, Kim S and Kim TS: The novel cytokine p43 induces IL-12 production in macrophages via NF-kappaB activation, leading to enhanced IFN-gamma production in CD4⁺ T cells. J Immunol. 176:256–264. 2006. View Article : Google Scholar
32	Kim E, Kim SH, Kim S, Cho D and Kim TS: AIMP1/p43 protein induces the maturation of bone marrow-derived dendritic cells with T helper type 1-polarizing ability. J Immunol. 180:2894–2902. 2008. View Article : Google Scholar : PubMed/NCBI
33	Kim SY, Son WS, Park MC, Kim CM, Cha BH, Yoon KJ, Lee SH and Park SG: ARS-interacting multi-functional protein 1 induces proliferation of human bone marrow-derived mesenchymal stem cells by accumulation of β-catenin via fibroblast growth factor receptor 2-mediated activation of Akt. Stem Cells Dev. 22:2630–2640. 2013. View Article : Google Scholar : PubMed/NCBI
34	Lee JH, Lee H, Joung YK, Jung KH, Choi JH, Lee DH, Park KD and Hong SS: The use of low molecular weight heparin-pluronic nanogels to impede liver fibrosis by inhibition the TGF-β/Smad signaling pathway. Biomaterials. 32:1438–1445. 2011. View Article : Google Scholar
35	Coffer PJ, Jin J and Woodgett JR: Protein kinase B (c-Akt): A multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 335:1–13. 1998. View Article : Google Scholar : PubMed/NCBI
36	Xu L, Hui AY, Albanis E, Arthur MJ, O'Byrne SM, Blaner WS, Mukherjee P, Friedman SL and Eng FJ: Human hepatic stellate cell lines, LX-1 and LX-2: New tools for analysis of hepatic fibrosis. Gut. 54:142–151. 2005. View Article : Google Scholar
37	Kretzschmar M, Doody J and Massagué J: Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature. 389:618–622. 1997. View Article : Google Scholar : PubMed/NCBI
38	Chen SJ, Yuan W, Mori Y, Levenson A, Trojanowska M and Varga J: Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: Involvement of Smad 3. J Invest Dermatol. 112:49–57. 1999. View Article : Google Scholar : PubMed/NCBI
39	Qi Z, Atsuchi N, Ooshima A, Takeshita A and Ueno H: Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Natl Acad Sci USA. 96:2345–2349. 1999. View Article : Google Scholar : PubMed/NCBI
40	Bataller R and Brenner DA: Liver fibrosis. J Clin Invest. 115:209–218. 2005. View Article : Google Scholar : PubMed/NCBI
41	Wynn TA: Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 117:524–529. 2007. View Article : Google Scholar : PubMed/NCBI
42	Han JM, Park SG, Lee Y and Kim S: Structural separation of different extracellular activities in aminoacyl-tRNA synthetase-interacting multi-functional protein, p43/AIMP1. Biochem Biophys Res Commun. 342:113–118. 2006. View Article : Google Scholar : PubMed/NCBI
43	Friedman SL: Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 275:2247–2250. 2000. View Article : Google Scholar : PubMed/NCBI
44	Gressner AM: Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Hepatol. 22(Suppl): 28–36. 1995.PubMed/NCBI
45	Bissell DM, Wang SS, Jarnagin WR and Roll FJ: Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest. 96:447–455. 1995. View Article : Google Scholar : PubMed/NCBI
46	Chen A and Davis BH: The DNA binding protein BTEB mediates acetaldehyde-induced, jun N-terminal kinase-dependent alphaI(I) collagen gene expression in rat hepatic stellate cells. Mol Cell Biol. 20:2818–2826. 2000. View Article : Google Scholar : PubMed/NCBI