Abstract
Liver fibrosis is characterized with the over expression and excessive accumulation of extracellular matrix proteins, including collagens. The causative factors in the over production of collagens are not fully understood. This study aims to test a hypothesis that activation of corticotropin releasing factor receptors up regulates the expression of collagen in hepatic stellate cells. In this study, human hepatic stellate cell line, LX-2 cells were cultured. Expression of collagens by LX-2 cells was assessed by real time RT-PCR, Western blotting. The results showed that, upon exposure to urocortin in the culture, LX-2 cells (a human hepatic stellate cell line) increased the expression of collagen IV (Col4) markedly. The exposure to urocortin also enhanced the levels of pTip60, H3K9, RNA polymerase II and forkhead box protein 3 at the collagen promoter locus as well as increase in the expression of Col4 mRNA and protein in the cells. Blocking p300 efficiently suppressed the urocortin-induced Col4 expression in LX-2 cells and unveiled an apoptosis-inducing effect of urocortin. In conclusion, activation of CRF receptors is capable of enforcing the production of Col4 by LX-2 cells via up regulating the p300 pathway, which may contribute to the development of liver fibrosis.
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: #81360598
Funding statement: This work was supported by a grant from the National Natural Science Foundation of China (#81360598).
Acknowledgments:
This work was supported by a grant from the National Natural Science Foundation of China (#81360598).
Conflict of interest statement: None to declare.
References
Alison, M.R., Islam, S., and Lim, S. (2009). Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J. Pathol. 217, 282–298.10.1002/path.2453Search in Google Scholar PubMed
An, R., Li, B., You, L.S., and Wang, X.H. (2015). Improvement of Kidney yang syndrome by icariin through regulating hypothalamus-pituitary-adrenal axis. Chin. J. Integr. Med. 21, 765–771.10.1007/s11655-015-2063-zSearch in Google Scholar PubMed
Breaux, M., Lewis, K., Valanejad, L., Iakova, P., Chen, F., Mo, Q., Medrano, E., Timchenko, L., and Timchenko, N. (2015). p300 regulates liver functions by controlling p53 and C/EBP family proteins through multiple signaling pathways. Mol. Cell. Biol. 35, 3005–3016.10.1128/MCB.00421-15Search in Google Scholar PubMed PubMed Central
Bugyei-Twum, A., Advani, A., Advani, S.L., Zhang, Y., Thai, K., Kelly, D.J., and Connelly, K.A. (2014). High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy. Cardiovasc. Diabetol. 13, 89.10.1186/1475-2840-13-89Search in Google Scholar PubMed PubMed Central
Chakraborty, J.B., Oakley, F., and Walsh, M.J. (2012). Mechanisms and biomarkers of apoptosis in liver disease and fibrosis. Int. J. Hepatol. 2012, 648915.10.1155/2012/648915Search in Google Scholar PubMed PubMed Central
DeLeve, L.D. (2015). Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61, 1740–1746.10.1002/hep.27376Search in Google Scholar PubMed PubMed Central
Geerts, A. (2001). History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin. Liver Dis. 21, 311–335.10.1055/s-2001-17550Search in Google Scholar PubMed
Ghosh, A.K., Bhattacharyya, S., Lafyatis, R., Farina, G., Yu, J., Thimmapaya, B., Wei, J., and Varga, J. (2013). p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-beta: epigenetic feed-forward amplification of fibrosis. J. Invest. Dermatol. 133, 1302–1310.10.1038/jid.2012.479Search in Google Scholar PubMed PubMed Central
Hannerfors, A.K., Hellgren, C., Schijven, D., Iliadis, S.I., Comasco, E., Skalkidou, A., Olivier, J.D., and Sundstrom-Poromaa, I. (2015). Treatment with serotonin reuptake inhibitors during pregnancy is associated with elevated corticotropin-releasing hormone levels. Psychoneuroendocrinology 58, 104–113.10.1016/j.psyneuen.2015.04.009Search in Google Scholar PubMed
Jiang, F., Liu, G.S., Dusting, G.J., and Chan, E.C. (2014). NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox. Biol. 2, 267–272.10.1016/j.redox.2014.01.012Search in Google Scholar PubMed PubMed Central
Kajdaniuk, D., Marek, B., Borgiel-Marek, H., and Kos-Kudla, B. (2013). Transforming growth factor beta1 (TGFbeta1) in physiology and pathology. Endokrynol. Pol. 64, 384–396.10.5603/EP.2013.0022Search in Google Scholar PubMed
Karsdal, M.A., Manon-Jensen, T., Genovese, F., and Kristensen, J.H. (2015). Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G807–830.10.1152/ajpgi.00447.2014Search in Google Scholar PubMed PubMed Central
Koh, S., Kim, J., Kim, B., Lee, K., and Kim, J. (2015). Restraint stress induces and exacerbates intestinal inflammation in interleukin-10 deficient mice. World J. Gastroenterol. 21, 8580–8587.10.3748/wjg.v21.i28.8580Search in Google Scholar PubMed PubMed Central
Lim, J.Y., Oh, M.A., Kim, W.H., Sohn, H.Y., and Park, S.I. (2012). AMP-activated protein kinase inhibits TGF-β-induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300. J. Cell. Physiol. 227, 1081–1089.10.1002/jcp.22824Search in Google Scholar PubMed
Liu, Y., Wang, L., Predina, J., Han, R., Beier, U.H., Wang, L.C., Kapoor, V., Bhatti, T.R., Akimova, T., Singhal, S., et al. (2013). Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity. Nat. Med. 19, 1173–1177.10.1038/nm.3286Search in Google Scholar PubMed PubMed Central
MaruYama, T. (2015). TGF-β-induced IκB-ζ controls Foxp3 gene expression. Biochem. Biophys. Res. Commun. 464, 586–589.10.1016/j.bbrc.2015.07.013Search in Google Scholar PubMed
Nagano, J., Nagase, S., Sudo, N., and Kubo, C. (2004). Psychosocial stress, personality, and the severity of chronic hepatitis C. Psychosomatics 45, 100–106.10.1176/appi.psy.45.2.100Search in Google Scholar PubMed
Paschos, K.A., Charsou, C., Constantinidis, T.C., Anagnostoulis, S., Lambropoulou, M., Papachristou, F., Simopoulos, K., and Chatzaki, E. (2010). Corticotropin-releasing hormone receptors mediate opposing effects in cholestasis-induced liver cell apoptosis. Endocrinology 151, 1704–1712.10.1210/en.2009-1208Search in Google Scholar PubMed
Paschos, K.A., Chouridou, E., Koureta, M., Lambropoulou, M., Kolios, G., and Chatzaki, E. (2013). The corticotropin releasing factor system in the liver: expression, actions and possible implications in hepatic physiology and pathology. Hormones (Athens) 12, 236–245.10.14310/horm.2002.1407Search in Google Scholar PubMed
Schmitz, M.K., Botte, D.A., Sotto, M.N., Borba, E.F., Bonfa, E., and de Mello, S.B. (2015). Increased corticotropin-releasing hormone (CRH) expression in cutaneous lupus lesions. Lupus 24, 854–861.10.1177/0961203315569335Search in Google Scholar PubMed
Simopoulos, C., Christodoulou, E., Lambropoulou, M., Tsaroucha, A.K., Kakolyris, S., Polychronidis, A., Karayiannakis, A.J., and Chatzaki, E. (2009). Neuropeptide urocortin 1 and its receptors are expressed in the human liver. Neuroendocrinology 89, 315–326.10.1159/000187136Search in Google Scholar PubMed
Sureka, B., Bansal, K., Patidar, Y., Rajesh, S., Mukund, A., and Arora, A. (2015). Neurologic manifestations of chronic liver disease and liver cirrhosis. Curr. Probl. Diagn. Radiol. 44, 449–461.10.1067/j.cpradiol.2015.03.004Search in Google Scholar PubMed
Tillinger, A., Nostramo, R., Kvetnansky, R., Serova, L., and Sabban, E.L. (2013). Stress-induced changes in gene expression of urocortin 2 and other CRH peptides in rat adrenal medulla: involvement of glucocorticoids. J. Neurochem. 125, 185–192.10.1111/jnc.12152Search in Google Scholar PubMed
Traussnigg, S., Kienbacher, C., Halilbasic, E., Rechling, C., Kazemi-Shirazi, L., Hofer, H., Munda, P., and Trauner, M. (2015). Challenges and management of liver cirrhosis: practical issues in the therapy of patients with cirrhosis due to NAFLD and NASH. Dig. Dis. 33, 598–607.10.1159/000375353Search in Google Scholar PubMed
Vere, C.C., Streba, C.T., Streba, L.M., Ionescu, A.G., and Sima, F. (2009). Psychosocial stress and liver disease status. World J. Gastroenterol. 15, 2980–2986.10.3748/wjg.15.2980Search in Google Scholar PubMed PubMed Central
Wang, Y., Wang, Y., Luo, M., Wu, H., Kong, L., Xin, Y., Cui, W., Zhao, Y., Wang, J., Liang, G., et al. (2015). Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation. Biochim. Biophys. Acta 1852, 34–46.10.1016/j.bbadis.2014.11.006Search in Google Scholar PubMed PubMed Central
Weiskirchen, R. and Tacke, F. (2014). Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary. Surg. Nutr. 3, 344–363.Search in Google Scholar
Yoshida, K., Murata, M., Yamaguchi, T., and Matsuzaki, K. (2014). TGF-β/Smad signaling during hepatic fibro-carcinogenesis (review). Int. J. Oncol. 45, 1363–1371.10.3892/ijo.2014.2552Search in Google Scholar PubMed PubMed Central
Zhao, Y., Wang, M.Y., Hao, K., Chen, X.Q., and Du, J.Z. (2013). CRHR1 mediates p53 transcription induced by high altitude hypoxia through ERK 1/2 signaling in rat hepatic cells. Peptides 44, 8–14.10.1016/j.peptides.2013.03.023Search in Google Scholar PubMed
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