Abstract
Excess scarring of the conjunctiva after glaucoma filtration surgery is a major cause of failure. Transforming growth factor (TGF)-β is critically involved in post-operative scarring. Lithium inhibits TGF-β-induced gene protein expression in corneal fibroblasts and inhibits TGF-β-induced epithelial mesenchymal transition. Here, we investigated the effects of LiCl on TGF-β1-mediated signaling pathways and on myofibroblast transdifferentiation of human Tenon’s capsule fibroblasts (HTFs). LiCl treatment reduced expression of TGF-β1-induced α-SMA expression in HTFs. LiCl also decreased Akt phosphorylation induced by TGF-β1. TGF-β1-induced α-SMA expression was significantly decreased by LY294002 and Akt siRNA indicating that these changes are mediated by the PI3K/Akt pathway. Thus, LiCl induces the suppression of transdifferentiation stimulated by TGF-β1 by the regulation of PI3K/Akt signaling in HTFs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baarsma HA, Spanjer AI, Haitsma G, Engelbertink LH, Meurs H, Jonker MR, Timens W, Postma DS, Kerstjens HA, Gosens R (2011) Activation of WNT/beta-catenin signaling in pulmonary fibroblasts by TGF-beta(1) is increased in chronic obstructive pulmonary disease. PLoS One 6:e25450
Choi SI, Kim BY, Dadakhujaev S, Jester JV, Ryu H, Kim TI, Kim EK (2011) Inhibition of TGFBIp expression by lithium: implications for TGFBI-linked corneal dystrophy therapy. Invest Ophthalmol Vis Sci 52:3293–3300
Chung EJ, Moon SW, Jung SA, Cho YJ, Kim SW, Lee JH (2010) Potentiation of bortezomib-induced apoptosis by TGF-beta in cultured human Tenon’s fibroblasts: contribution of the PI3K/Akt signaling pathway. Invest Ophthalmol Vis Sci 51:6232–6237
Cordeiro MF (2002) Beyond mitomycin: TGF-beta and wound healing. Prog Retin Eye Res 21:75–89
Cordeiro MF (2003) Role of transforming growth factor beta in conjunctival scarring. Clin Sci (Lond) 104:181–187
Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122:103–111
Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426
Grisanti S, Szurman P, Warga M, Kaczmarek R, Ziemssen F, Tatar O, Bartz-Schmidt KU (2005) Decorin modulates wound healing in experimental glaucoma filtration surgery: a pilot study. Invest Ophthalmol Vis Sci 46:191–196
Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, Thannickal VJ (2007) Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal 19:761–771
Khaw P, Grehn F, Hollo G, Overton B, Wilson R, Vogel R, Smith Z (2007) A phase III study of subconjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy. Ophthalmology 114:1822–1830
Martin MM, Buckenberger JA, Jiang J, Malana GE, Knoell DL, Feldman DS, Elton TS (2007) TGF-beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways. Am J Physiol Lung Cell Mol Physiol 293:L790–L799
Masszi A, Fan L, Rosivall L, McCulloch CA, Rotstein OD, Mucsi I, Kapus A (2004) Integrity of cell–cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol 165:1955–1967
Meyer-ter-Vehn T, Sieprath S, Katzenberger B, Gebhardt S, Grehn F, Schlunck G (2006) Contractility as a prerequisite for TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. Invest Ophthalmol Vis Sci 47:4895–4904
Michalik M, Wojcik KA, Jakiela B, Szpak K, Pierzchalska M, Sanak M, Madeja Z, Czyz J (2012) Lithium attenuates TGF-beta(1)-induced fibroblasts to myofibroblasts transition in bronchial fibroblasts derived from asthmatic patients. J Allergy (Cairo) 2012:206109
Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700
Stump RJ, Lovicu FJ, Ang SL, Pandey SK, McAvoy JW (2006) Lithium stabilizes the polarized lens epithelial phenotype and inhibits proliferation, migration, and epithelial mesenchymal transition. J Pathol 210:249–257
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363
van Noort M, Meeldijk J, van der Zee R, Destree O, Clevers H (2002) Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem 277:17901–17905
Wilkes MC, Mitchell H, Penheiter SG, Dore JJ, Suzuki K, Edens M, Sharma DK, Pagano RE, Leof EB (2005) Transforming growth factor-beta activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res 65:10431–10440
Young W (2009) Review of lithium effects on brain and blood. Cell Transpl 18:951–975
Zhang K, Rekhter MD, Gordon D, Phan SH (1994) Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol 145:114–125
Acknowledgments
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology Grant 2010-0009023.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chung, E.J., Sohn, Y.H., Kwon, S.H. et al. Lithium chloride inhibits TGF-β1-induced myofibroblast transdifferentiation via PI3K/Akt pathway in cultured fibroblasts from Tenon’s capsule of the human eye. Biotechnol Lett 36, 1217–1224 (2014). https://doi.org/10.1007/s10529-014-1487-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10529-014-1487-4