Cytomegalovirus Infection Triggers the Secretion of the PPARgamma Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures.
[en] INTRODUCTION: Congenital infection by human cytomegalovirus (HCMV) is a leading cause of congenital abnormalities of the central nervous system. Placenta infection by HCMV allows for viral spread to fetus and may result in intrauterine growth restriction, preeclampsia-like symptoms, or miscarriages. We previously reported that HCMV activates peroxisome proliferator-activated receptor gamma (PPARgamma) for its own replication in cytotrophoblasts. Here, we investigated the molecular bases of PPARgamma activation in infected cytotrophoblasts. RESULTS: We show that onboarded cPLA2 carried by HCMV particles is required for effective PPARgamma activation in infected HIPEC cytotrophoblasts, and for the resulting inhibition of cell migration. Natural PPARgamma agonists are generated by PLA2 driven oxidization of linoleic and arachidonic acids. Therefore, using HPLC coupled with mass spectrometry, we disclosed that cellular and secreted levels of 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE) were significantly increased in and from HIPEC cytotrophoblasts at soon as 6 hours post infection. 13-HODE treatment of uninfected HIPEC recapitulated the effect of infection (PPARgamma activation, migration impairment). We found that infection of histocultures of normal, first-term, human placental explants resulted in significantly increased levels of secreted 15-HETE and 13-HODE. CONCLUSION: Our findings reveal that 15-HETE and 13-HODE could be new pathogenic effectors of HCMV congenital infection They provide a new insight about the pathogenesis of congenital infection by HCMV.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Leghmar, Kaoutar
Cenac, Nicolas
Rolland, Maude ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo of Molecular Immunol. and Signal Transduction
Martin, Helene
Rauwel, Benjamin
Bertrand-Michel, Justine
Le Faouder, Pauline
Benard, Melinda
Casper, Charlotte
Davrinche, Christian
Fournier, Thierry
Chavanas, Stephane
Language :
English
Title :
Cytomegalovirus Infection Triggers the Secretion of the PPARgamma Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures.
Publication date :
2015
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Boppana SB, Ross SA, Fowler KB. Congenital Cytomegalovirus Infection: Clinical Outcome. Clinical Infectious Diseases. 2013; 57(suppl 4):S178-S81. doi: 10.1093/cid/cit629 PMID: 24257422
Cannon MJ. Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol. 2009; 46 Suppl 4:S6-10. PMID: 19800841. doi: 10.1016/j.jcv.2009.09.002
Cheeran MCJ, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev. 2009; 22(1):99-126, Table of Contents. doi: 10.1128/CMR.00023-08 PMID: 19136436
Fisher S, Genbacev O, Maidji E, Pereira L. Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: implications for transmission and pathogenesis. J Virol. 2000; 74(15):6808-20. PMID: 10888620.
Pereira L. Have We Overlooked Congenital Cytomegalovirus Infection as a Cause of Stillbirth? Journal of Infectious Diseases. 2011; 203(11):1510-2. doi: 10.1093/infdis/jir126 PMID: 21592978
Pereira L, Maidji E, McDonagh S, Tabata T. Insights into viral transmission at the uterine-placental interface. Trends in Microbiology. 2005; 13(4):164-74. PMID: 15817386
Pereira L, Petitt M, Fong A, Tsuge M, Tabata T, Fang-Hoover J, et al. Intrauterine Growth Restriction Caused by Underlying Congenital Cytomegalovirus Infection. Journal of Infectious Diseases. 2014; 209(10):1573-84. doi: 10.1093/infdis/jiu019 PMID: 24403553
Rauwel B, Mariame B, Martin H, Nielsen R, Allart S, Pipy B, et al. Activation of peroxisome proliferator-activated receptor gamma by human cytomegalovirus for de novo replication impairs migration and invasiveness of cytotrophoblasts from early placentas. J Virol. 2010; 84(6):2946-54. PMID: 20042507. doi: 10.1128/JVI.01779-09
Fournier T, Tsatsaris V, Handschuh K, Evain-Brion D. PPARs and the Placenta. Placenta. 2007; 28(2-3):65-76. PMID: 16834993
Pavan L, Tarrade A, Hermouet A, Delouis C, Titeux M, Vidaud M, et al. Human invasive trophoblasts transformed with simian virus 40 provide a new tool to study the role of PPARg in cell invasion process. Carcinogenesis. 2003; 24(8):1325-36. doi: 10.1093/carcin/bgg074 PMID: 12807721
Le Faouder P, Baillif V, Spreadbury I, Motta J-P, Rousset P, Chêne G, et al. LC-MS/MS method for rapid and concomitant quantification of pro-inflammatory and pro-resolving polyunsaturated fatty acid metabolites. Journal of Chromatography B. 2013; 932(0):123-33.
Lopez H, Benard M, Saint-Aubert E, Baron M, Martin H, Al Saati T, et al. Novel model of placental tissue explants infected by cytomegalovirus reveals different permissiveness in early and term placentae and inhibition of indoleamine 2,3-dioxygenase activity. Placenta. 2011; 32(7):522-30. doi: 10.1016/j.placenta.2011.04.016 PMID: 21605903
Six DA, Dennis EA. The expanding superfamily of phospholipaseA2 enzymes: classification and characterization. Biochimica et Biophysica Acta(BBA) - Molecular and Cell Biology of Lipids. 2000; 1488 (1â€"2):1-19.
Allal C, Buisson-Brenac C, Marion V, Claudel-Renard C, Faraut T, Dal Monte P, et al. Human Cytomegalovirus Carries a Cell-Derived Phospholipase A2 Required for Infectivity. Journal of Virology. 2004; 78 (14):7717-26. doi: 10.1128/jvi.78.14.7717-7726.2004 PMID: 15220446
Rak-Mardyla A, Karpeta A. Rosiglitazone stimulates peroxisome proliferator-activated receptor gamma expression and directly affects in  vitro steroidogenesis in porcine ovarian follicles. Theriogenology. 2014; 82(1):1-9. doi: 10.1016/j.theriogenology.2014.02.016 PMID: 24681211
Leesnitzer LM, Parks DJ, Bledsoe RK, Cobb JE, Collins JL, Consler TG, et al. Functional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662. Biochemistry. 2002; 41(21):6640-50. PMID: 12022867
Schild RL, Schaiff WT, Carlson MG, Cronbach EJ, Nelson DM, Sadovsky Y. The Activity of PPARg in Primary Human Trophoblasts Is Enhanced by Oxidized Lipids. Journal of Clinical Endocrinology & Metabolism. 2002; 87(3):1105-10. doi: 10.1210/jc.87.3.1105
Wittwer J, Hersberger M. The two faces of the 15-lipoxygenase in atherosclerosis. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2007; 77(2):67-77.
Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, et al. Interleukin-4-dependentproduction of PPAR-[gamma] ligands in macrophages by 12/15-lipoxygenase. Nature. 1999; 400(6742):378-82. PMID: 10432118
Nagy L, Tontonoz P, Alvarez JGA, Chen H, Evans RM. Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPARÎ3. Cell. 1998; 93(2):229-40. PMID: 9568715
Daynes RA, Jones DC. Emerging roles of PPARS in inflammation and immunity. Nat Rev Immunol. 2002; 2(10):748-59. PMID: 12360213
Wang Y, Zhu D, An Y, Sun J, Cai L, Zheng J. Preeclampsia activates 15-lipoxygenase and its metabolite 15-hydroxyeicosatetraenoic acid enhances constriction in umbilical arteries. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2011; 86(1â€"2):79-84.
Johnson RD, Polakoski KL, Huang X, Sadovsky Y, Nelson DM. The release of 15-hydroxyeicosatetraenoic acid by human placental trophoblast is increased in preeclampsia. American Journal of Obstetrics and Gynecology. 1998; 178(1, Part1):54-8. PMID: 9465803
Yuan D, Ran Y, Liu Q, Zhang Y, Li H, Li P, et al. Enhancement of the HIF-1alpha and 15-LO/15-HETE Axis Promotes Hypoxia-Induced Endothelial Proliferation in Preeclamptic Pregnancy. PLoSONE. 2014; 9(5):e96510. doi: 10.1371/journal.pone.0096510 PMID: 24796548
Wu M-Y, Yang R-S, Lin T-H, Tang C-H, Chiu Y-C, Liou H-C, et al. Enhancement of PLGF production by 15-(S)-HETE via PI3K-Akt, NF-kB and COX-2 pathways in rheumatoid arthritis synovial fibroblast. European Journal of Pharmacology. 2013; 714(1â€"3):388-96. doi: 10.1016/j.ejphar.2013.07.010 PMID: 23872401
Torry DS, Ahn H, Barnes EL, Torry RJ. Placenta growth factor: potential role in pregnancy. Am J Reprod Immunol. 1999; 41(1):79-85. PMID: 10097790.
Maidji E, Nigro G, Tabata T, McDonagh S, Nozawa N, Shiboski S, et al. Antibody Treatment Promotes Compensation for Human Cytomegalovirus-Induced Pathogenesis and a Hypoxia-Like Condition in Placentas with Congenital Infection. The American Journal of Pathology. 2010; 177(3):1298-310. doi: 10.2353/ajpath.2010.091210 PMID: 20651234
Subbarayan V, Krieg P, Hsi LC, Kim J, Yang P, Sabichi AL, et al. 15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor [gamma]. Oncogene. 2006; 25(44):6015-25. PMID: 16682954
Majed BH, Khalil RA. Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn. Pharmacological Reviews. 2012; 64(3):540-82. doi: 10.1124/pr.111.004770 PMID: 22679221
Fei J, Cook C, Santanam N. Omega-6 lipids regulate PPAR turnover via reciprocal switch between PGC-1 alpha and ubiquitination. Atherosclerosis. 2012; 222(2):395-401. PMID: 22464285. doi: 10.1016/j.atherosclerosis.2012.02.040
Pavan L, Hermouet A, Tsatsaris V, Thérond P, Sawamura T, Evain-Brion DI, et al. Lipids from Oxidized Low-Density Lipoprotein Modulate Human Trophoblast Invasion: Involvement of Nuclear Liver X Receptors. Endocrinology. 2004; 145(10):4583-91. doi: 10.1210/en.2003-1747 PMID: 15242983
Winkler K, Wetzka B, Hoffmann MM, Friedrich I, Kinner M, Baumstark MW, et al. Low Density Lipoprotein (LDL) Subfractions during Pregnancy: Accumulation of Buoyant LDL with Advancing Gestation. Journal of Clinical Endocrinology & Metabolism. 2000; 85(12):4543-50. doi: 10.1210/jc.85.12.4543
Pavan L, Tsatsaris V, Hermouet A, Therond P, Evain-Brion D, Fournier T. Oxidized Low-Density Lipoproteins Inhibit Trophoblastic Cell Invasion. Journal of Clinical Endocrinology & Metabolism. 2004; 89 (4):1969-72. doi: 10.1210/jc.2003-032042
Coutant F, Agaugue S, Perrin-Cocon L, Andre P, Lotteau V. Sensing Environmental Lipids by Dendritic Cell Modulates Its Function. The Journal of Immunology. 2004; 172(1):54-60. doi: 10.4049/jimmunol.172.1.54 PMID: 14688309
Gunthorpe MJ, Szallasi A. Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms. Curr Pharm Des. 2008; 14(1):32-41. PMID: 18220816.
Toth A, Boczan J, Kedei N, Lizanecz E, Bagi Z, Papp Z, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Molecular Brain Research. 2005; 135(1-2):162-8. PMID: 15857679
Alsalem M, Wong A, Millns P, Arya PH, Chan MSL, Bennett A, et al. The contribution of the endogenous TRPV1 ligands 9-HODE and 13-HODEto nociceptive processing and their role in peripheral inflammatory pain mechanisms. British Journal of Pharmacology. 2013; 168(8):1961-74. doi: 10.1111/bph.12092 PMID: 23278358
Holdsworth-Carson SJ, Lim R, Mitton A, Whitehead C, Rice GE, Permezel M, et al. Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: Gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta. 2010; 31(3):222-9. doi: 10.1016/j.placenta.2009.12.009 PMID: 20045185
Staff AC, Dechend R, Pijnenborg R. Learning From the Placenta: Acute Atherosis and Vascular Remodeling in Preeclampsia-Novel Aspects for Atherosclerosis and Future Cardiovascular Health. Hypertension. 2010; 56(6):1026-34. doi: 10.1161/hypertensionaha.110.157743 PMID: 20956732