Abstract
Aims
The glycoprotein progranulin directly binds to TNF-receptors and thereby can antagonize the inflammatory effects of TNF-α. Here we analyzed the impact of both cytokines on cytotoxicity and viability of trophoblast cells.
Methods
Isolated villous first trimester human trophoblast cells and the human choriocarcinoma cell line BeWo were treated with recombinant human progranulin and TNF-α. Analyses were performed by LDH- and MTT-assay and measurement of caspase-8-activity.
Results
Progranulin treatment showed some cytoprotective effects on isolated trophoblast cells. However, TNF-α-induced apoptosis was not antagonized by addition of progranulin. Effects were similar, but more pronounced in BeWo cells.
Conclusion
The cytoprotective activity of progranulin on trophoblast cells in vitro was only weak and of doubtful biologic relevance. It was not able to antagonize TNF-α. Future studies should focus on possible paracrine activities of progranulin.
Similar content being viewed by others
References
Levy R, Smith SD, Sadovsky Y, Nelson DM (2000) Apoptosis in placental development remodelling and pathology 215:27–39
Huppertz B, Kadyrov M, Kingdom JC (2006) Apoptosis and its role in the trophoblast. Am J Obstet Gynecol 195:29–39
Longtine MS, Chen B, Odibo AO, Zhong Y, Nelson DM (2012) Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR. Placenta 33:352–359
Huppertz B (2011) Placental pathology in pregnancy complications. Thromb Res 127(Suppl 3):S96–S99
Haider S, Knofler M (2009) Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium. Placenta 30:111–123
Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, Syed NM, Lai Y, Lin EA, Kong L, Su J, Yin F, Ding AH, Zanin-Zhorov A, Dustin ML, Tao J, Craft J, Yin Z, Feng JQ, Abramson SB, Yu XP, Liu CJ (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332:478–484
Desmarais JA, Cao M, Bateman A, Murphy BD (2008) Spatiotemporal expression pattern of progranulin in embryo implantation and placenta formation suggests a role in cell proliferation, remodeling, and angiogenesis. Reproduction 136:247–257
Stubert J, Richter DU, Gerber B, Briese V (2011) Expression pattern of progranulin in the human placenta and its effect on cell proliferation in the choriocarcinoma cell line BeWo. J Reprod Dev 57:229–235
Stubert J, Schattenberg F, Richter DU, Dieterich M, Briese V (2012) Trophoblastic progranulin expression is upregulated in cases of fetal growth restriction and preeclampsia. J Perinat Med 40:475–481
Sitras V, Paulssen RH, Gronaas H, Leirvik J, Hanssen TA, Vartun A, Acharya G (2009) Differential placental gene expression in severe preeclampsia. Placenta 30:424–433
Yui J, Garcia-Lloret M, Wegmann TG, Guilbert LJ (1994) Cytotoxicity of tumour necrosis factor-alpha and gamma-interferon against primary human placental trophoblasts. Placenta 15:819–835
Yui J, Hemmings D, Garcia-Lloret M, Guilbert LJ (1996) Expression of the human p55 and p75 tumor necrosis factor receptors in primary villous trophoblasts and their role in cytotoxic signal transduction. Biol Reprod 55:400–409
Cackovic M, Buhimschi CS, Zhao G, Funai EF, Norwitz ER, Kuczynski E, Lockwood CJ, Buhimschi IA (2008) Fractional excretion of tumor necrosis factor-alpha in women with severe preeclampsia. Obstet Gynecol 112:93–100
Todoric J, Handisurya A, Perkmann T, Knapp B, Wagner O, Tura A, Pacini G, Esterbauer H, Kautzky-Willer A (2012) Circulating progranulin levels in women with gestational diabetes mellitus and healthy controls during and after pregnancy. Eur J Endocrinol 167:561–567
Youn BS, Bang SI, Kloting N, Park JW, Lee N, Oh JE, Pi KB, Lee TH, Ruschke K, Fasshauer M, Stumvoll M, Bluher M (2009) Serum progranulin concentrations may be associated with macrophage infiltration into omental adipose tissue. Diabetes 58:627–636
Bateman A, Bennett HP (1998) Granulins: the structure and function of an emerging family of growth factors. J Endocrinol 158:145–151
He Z, Bateman A (2003) Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 81:600–612
Kessenbrock K, Frohlich L, Sixt M, Lammermann T, Pfister H, Bateman A, Belaaouaj A, Ring J, Ollert M, Fassler R, Jenne DE (2008) Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest 118:2438–2447
Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, Lacomis L, Erdjument-Bromage H, Tempst P, Wright CD, Ding A (2002) Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 111:867–878
Bateman A, Bennett HP (2009) The granulin gene family: from cancer to dementia. BioEssays 31:1245–1254
He Z, Bateman A (1999) Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo. Cancer Res 59:3222–3229
Jian J, Zhao S, Tian Q, Gonzalez-Gugel E, Mundra JJ, Uddin SM, Liu B, Richbourgh B, Brunetti R, Liu CJ (2013) Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains. FEBS Lett 587:3428–3436
Uddin SM, Mundra JJ, Jian J, Tian Q, Gonzalez-Gugel E, Richbourgh B, Liu CJ (2014) Progranulin inhibition of TNFalpha. Immunol Cell Biol 92:299–300
Toh H, Chitramuthu BP, Bennett HP, Bateman A (2011) Structure, function, and mechanism of progranulin; the brain and beyond. J Mol Neurosci 45:538–548
Qin J, Diaz-Cueto L, Schwarze JE, Takahashi Y, Imai M, Isuzugawa K, Yamamoto S, Chang KT, Gerton GL, Imakawa K (2005) Effects of progranulin on blastocyst hatching and subsequent adhesion and outgrowth in the mouse. Biol Reprod 73:434–442
Orendi K, Kivity V, Sammar M, Grimpel Y, Gonen R, Meiri H, Lubzens E, Huppertz B (2011) Placental and trophoblastic in vitro models to study preventive and therapeutic agents for preeclampsia. Placenta 32(Suppl):S49–S54
Kleinberger G, Wils H, Ponsaerts P, Joris G, Timmermans JP, Van BC, Kumar-Singh S (2010) Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem 115:735–747
Xu J, Xilouri M, Bruban J, Shioi J, Shao Z, Papazoglou I, Vekrellis K, Robakis NK (2011) Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32:2326
Guerra RR, Kriazhev L, Hernandez-Blazquez FJ, Bateman A (2007) Progranulin is a stress-response factor in fibroblasts subjected to hypoxia and acidosis. Growth Factors 25:280–285
Piscopo P, Rivabene R, Adduci A, Mallozzi C, Malvezzi-Campeggi L, Crestini A, Confaloni A (2010) Hypoxia induces up-regulation of progranulin in neuroblastoma cell lines. Neurochem Int 57:893–898
Knofler M, Mosl B, Bauer S, Griesinger G, Husslein P (2000) TNF-alpha/TNFRI in primary and immortalized first trimester cytotrophoblasts. Placenta 21:525–535
Crocker IP, Tansinda DM, Jones CJ, Baker PN (2004) The influence of oxygen and tumor necrosis factor-alpha on the cellular kinetics of term placental villous explants in culture. J Histochem Cytochem 52:749–757
Huppertz B (2010) IFPA Award in Placentology Lecture: biology of the placental syncytiotrophoblast—myths and facts. Placenta 31(Suppl):S75–S81
Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T, Maruo T (2002) Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 186:158–166
Sharp AN, Heazell AE, Crocker IP, Mor G (2010) Placental apoptosis in health and disease. Am J Reprod Immunol 64:159–169
Wang Y, Walsh SW (1996) TNF alpha concentrations and mRNA expression are increased in preeclamptic placentas. J Reprod Immunol 32:157–169
Almasry SM, Eldomiaty MA, Elfayomy AK, Habib FA (2012) Expression pattern of tumor necrosis factor alpha in placentae of idiopathic fetal growth restriction. J Mol Histol 43:253–261
Kharfi A, Bureau M, Giguere Y, Moutquin JM, Forest JC (2006) Dissociation between increased apoptosis and expression of the tumor necrosis factor-alpha system in term placental villi with preeclampsia. Clin Biochem 39:646–651
Chen LM, Liu B, Zhao HB, Stone P, Chen Q, Chamley L (2010) IL-6, TNFalpha and TGFbeta promote nonapoptotic trophoblast deportation and subsequently causes endothelial cell activation. Placenta 31:75–80
Toh H, Cao M, Daniels E, Bateman A (2013) Expression of the growth factor progranulin in endothelial cells influences growth and development of blood vessels: a novel mouse model. PLoS ONE 8:e64989
Huppertz B (2008) Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 51:970–975
Hwang HJ, Jung TW, Hong HC, Choi HY, Seo JA, Kim SG, Kim NH, Choi KM, Choi DS, Baik SH, Yoo HJ (2013) Progranulin protects vascular endothelium against atherosclerotic inflammatory reaction via Akt/eNOS and nuclear factor-kappaB pathways. PLoS ONE 8:e76679
Conflict of interest
The authors reported of no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
404_2014_3296_MOESM1_ESM.tif
Supplemental Figure Representative photographs of isolated first trimester trophoblast cells in culture after an incubation time of 48 h. The non-adherent cells show a spheroid shape and aggregate to pseudosyncytial clusters. Analysis of cell morphology did not reveal obvious differences between different groups. Scale bar = 100 µm Supplementary material 1 (TIFF 2541 kb)
Rights and permissions
About this article
Cite this article
Stubert, J., Waldmann, K., Dieterich, M. et al. Progranulin shows cytoprotective effects on trophoblast cells in vitro but does not antagonize TNF-α-induced apoptosis. Arch Gynecol Obstet 290, 867–873 (2014). https://doi.org/10.1007/s00404-014-3296-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-014-3296-3