NIM811 downregulates transforming growth factor‑β signal transduction in vivo and in vitro

Chen,Jing; Liu,Dian‑Gang; Wang,Hui; Wu,Xiao‑Ning; Cong,Min; You,Hong; Jia,Ji‑Dong

doi:10.3892/mmr.2015.4572

January-2016 Volume 13 Issue 1

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

January-2016 Volume 13 Issue 1

Full Size Image

Article

NIM811 downregulates transforming growth factor‑β signal transduction in vivo and in vitro

Authors:
- Jing Chen
- Dian‑Gang Liu
- Hui Wang
- Xiao‑Ning Wu
- Min Cong
- Hong You
- Ji‑Dong Jia
View Affiliations / Copyright

Affiliations: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China, Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
Pages: 522-528
|
Published online on: November 16, 2015

https://doi.org/10.3892/mmr.2015.4572
Expand metrics +

Abstract

Liver fibrosis is the common histological feature of a number of chronic liver diseases, and leads to cirrhosis and hepatocellular carcinoma (HCC). It has been demonstrated that N‑methyl‑4‑isoleucine cyclosporine (NIM811) attenuates CCl4‑induced liver fibrosis and inflammation in rats. The present study investigated whether NIM811 downregulated transforming growth factor (TGF)‑β signaling in rats with CCl4‑induced liver fibrosis and in HSC‑T6 cells. Liver tissues were obtained from rats with CCl4‑induced liver fibrosis, with or without NIM811 treatment. HSC‑T6 cells were cultured with or without NIM811 for 18 h under serum‑free conditions. Expression of collagen I, α‑smooth muscle actin (α‑SMA), TGF‑β1, TGF‑β receptor I (TβR‑I) and TGF‑β pathway downstream signaling molecules were measured by reverse transcription‑quantitative polymerase chain reaction and/or western blotting. Collagen I and TGF‑β1 content in the cell supernatant was measured by ELISA. NIM811 profoundly inhibited collagen I, α‑SMA, TGF‑β1 and TβR‑I expression in the liver of CCl4‑treated rats. Phosphorylation of Smad2, 3 and 1/5/8 was decreased in the liver of NIM811‑treated groups, accompanied by increased In addition, Smad7 expression compared with the CCl4‑treated rats. NIM811 inhibited collagen I, TGF‑β1 and TβR‑I expression in HSC‑T6 cells. Smad1 mRNA and phospho‑Smad1/5/8 protein levels decreased following NIM811 treatment, accompanied by increased Smad7 expression in HSC‑T6 cells compared with normal controls. Furthermore, NIM811 also inhibited collagen I mRNA expression in the liver of rats with CCl4‑induced liver fibrosis and in HSC‑T6 cells. The results suggest that the antifibrotic effect of NIM811 was due to the inhibition of TGF‑β1 and its downstream signaling molecules.

View Figures

View References

1	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
2	Moreno M and Bataller R: Cytokines and reninangiotensin system signaling in hepatic fibrosis. Clin Liver Dis. 12:825–852. 2008. View Article : Google Scholar
3	Gressner OA, Lahme B, Demirci I, Gressner AM and Weiskirchen R: Differential effects of TGF-beta on connective tissue growth factor (CTGF/CCN2) expression in hepatic stellate cells and hepatocytes. J Hepatol. 47:699–710. 2007. View Article : Google Scholar : PubMed/NCBI
4	Wynn TA: Cellular and molecular mechanisms of fibrosis. J Pathol. 214:199–210. 2008. View Article : Google Scholar
5	Parsons CJ, Takashima M and Rippe RA: Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol. 22(Suppl 1): S79–S84. 2007. View Article : Google Scholar : PubMed/NCBI
6	Casini A, Pinzani M, Milani S, Grappone C, Galli G, Jezequel AM, Schuppan D, Rotella CM and Surrenti C: Regulation of extracellular matrix synthesis by transforming growth factor beta 1 in human fat-storing cells. Gastroenterology. 105:245–253. 1993.PubMed/NCBI
7	Kohjima M, Enjoji M, Higuchi N, Kotoh K, Kato M, Takayanagi R and Nakamuta M: NIM811, a nonimmunosuppressive cyclosporine analogue, suppresses collagen production and enhances collagenase activity in hepatic stellate cells. Liver Int. 27:1273–1281. 2007.PubMed/NCBI
8	Waldmeier PC, Feldtrauer JJ, Qian T and Lemasters JJ: Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol. 62:22–29. 2002. View Article : Google Scholar : PubMed/NCBI
9	Theruvath TP, Zhong Z, Pediaditakis P, Ramshesh VK, Currin RT, Tikunov A, Holmuhamedov E and Lemasters J: Minocycline and N-methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition. Hepatology. 47:236–246. 2008. View Article : Google Scholar
10	Zhong Z, Theruvath TP, Currin RT, Waldmeier PC and Lemasters JJ: NIM811, a mitochondrial permeability transition inhibitor, prevents mitochondrial depolarization in small-for-size rat liver grafts. Am J Transplant. 7:1103–1111. 2007. View Article : Google Scholar : PubMed/NCBI
11	Kohjima M, Enjoji M, Higuchi N, Kotoh K, Kato M, Takayanagi R and Nakamuta M: NIM811, a nonimmunosuppressive cyclosporine analogue, suppresses collagen production and enhances collagenase activity in hepatic stellate cells. Liver Int. 27:1273–1281. 2007.PubMed/NCBI
12	Wang H, Zhang Y, Wang T, You H and Jia J: N-methyl-4-isoleucine cyclosporine attenuates CCl-induced liver fibrosis in rats by interacting with cyclophilin B and D. J Gastroenterol Hepatol. 26:558–567. 2011. View Article : Google Scholar : PubMed/NCBI
13	Wang H, Zhang Y, Wang T, You H and Jia J: N-methyl-4-isoleucine cyclosporine attenuates CCl-induced liver fibrosis in rats by interacting with cyclophilin B and D. J Gastroenterol Hepatol. 26:558–567. 2011. View Article : Google Scholar : PubMed/NCBI
14	Dooley S, Delvoux B, Lahme B, Mangasser-Stephan K and Gressner AM: Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology. 31:1094–1106. 2000. View Article : Google Scholar : PubMed/NCBI
15	Friedman SL: Hepatic fibrosis-overview. Toxicology. 254:120–129. 2008. View Article : Google Scholar : PubMed/NCBI
16	Breitkopf K, Godoy P, Ciuclan L, Singer MV and Dooley S: TGF-beta/Smad signaling in the injured liver. Z Gastroenterol. 44:57–66. 2006. View Article : Google Scholar : PubMed/NCBI
17	Border WA and Noble NA: Transforming growth factor beta in tissue fibrosis. N Engl J Med. 331:1286–1292. 1994. View Article : Google Scholar : PubMed/NCBI
18	Kolodziejczyk SM and Hall BK: Signal transduction and TGF-beta superfamily receptors. Biochem Cell Biol. 74:299–314. 1996. View Article : Google Scholar : PubMed/NCBI
19	Miyazawa K, Shinozaki M, Hara T, Furuya T and Miyazono K: Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells. 7:1191–1204. 2002. View Article : Google Scholar : PubMed/NCBI
20	Attisano L and Wrana JL: Signal transduction by the TGF-beta superfamily. Science. 296:1646–1647. 2002. View Article : Google Scholar : PubMed/NCBI
21	Higashiyama R, Inagaki Y, Hong YY, Kushida M, Nakao S, Niioka M, Watanabe T, Okano H, Matsuzaki Y, Shiota G and Okazaki I: Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology. 45:213–222. 2007. View Article : Google Scholar
22	Inagaki Y and Okazaki I: Emerging insights into transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut. 56:284–292. 2007. View Article : Google Scholar : PubMed/NCBI
23	Wiercinska E, Wickert L, Denecke B, Said HM, Hamzavi J, Gressner AM, Thorikay M, ten Dijke P, Mertens PR, Breitkopf Ka and Dooley S: Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells. Hepatology. 43:1032–1041. 2006. View Article : Google Scholar : PubMed/NCBI
24	Miyazono K, Kusanagi K and Inoue H: Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol. 187:265–276. 2001. View Article : Google Scholar : PubMed/NCBI
25	Friedman SL, Yamasaki G and Wong L: Modulation of transforming growth factor beta receptors of rat lipocytes during the hepatic wound healing response. Enhanced binding and reduced gene expression accompany cellular activation in culture and in vivo. J Biol Chem. 269:10551–10558. 1994.PubMed/NCBI
26	Zebedee Z and Hara E: Id proteins in cell cycle control and cellular senescence. Oncogene. 20:8317–8325. 2001. View Article : Google Scholar
27	Li L, Zhao XY and Wang BE: Down-regulation of transforming growth factor beta 1/activin receptor-like kinase 1 pathway gene expression by herbal compound 861 is related to deactivation of LX-2 cells. World J Gastroenterol. 14:2894–2899. 2008. View Article : Google Scholar : PubMed/NCBI
28	Itoh S, Itoh F, Goumans MJ and Ten Dijke P: Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem. 267:6954–6967. 2000. View Article : Google Scholar : PubMed/NCBI
29	Itóh S, Landström M, Hermansson A, Itoh F, Heldin CH, Heldin NE and ten Dijke P: Transforming growth factor beta1 induces nuclear export of inhibitory Smad7. J Biol Chem. 273:29195–29201. 1998. View Article : Google Scholar : PubMed/NCBI
30	Friedman SL: Hepatic stellate cells: Protean, multifunctional and enigmatic cells of the liver. Physiol Rev. 88:125–172. 2008. View Article : Google Scholar : PubMed/NCBI
31	Pinzani M: PDGF and signal transduction in hepatic stellate cells. Front Biosci. 7:d1720–d1726. 2002. View Article : Google Scholar : PubMed/NCBI
32	Borkham-Kamphorst E, van Roeyen CR, Ostendorf T, Floege J, Gressner AM and Weiskirchen R: Pro-fibrogenic potential of PDGF-D in liver fibrosis. J Hepatol. 46:1064–1074. 2007. View Article : Google Scholar : PubMed/NCBI
33	Pinzani M and Marra F: Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis. 21:397–416. 2001. View Article : Google Scholar : PubMed/NCBI
34	Lechuga CG, Hernandez-Nazara ZH, Hernández E, Bustamante M, Desierto G, Cotty A, Dharker N, Choe M and Rojkind M: PI3K is involved in PDGF-beta receptor upregulation post-PDGF-BB treatment in mouse HSC. Am J Physiol Gastrointest Liver Physiol. 291:G1051–G1061. 2006. View Article : Google Scholar : PubMed/NCBI
35	Harder KW, Owen P, Wong LK, Aebersold R, Clark-Lewis I and Jirik FR: Characterization and kinetic analysis of the intracellular domain of human protein tyrosine phosphatase beta (HPTP beta) using synthetic phosphopeptides. Biochem J. 298:395–401. 1994. View Article : Google Scholar : PubMed/NCBI
36	Wong L, Yamasaki G, Johnson RJ and Friedman SL: Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture. J Clin Invest. 94:1563–1569. 1994. View Article : Google Scholar : PubMed/NCBI