Pregnancy is a state of immunotolerance, and pregnancy outcome is strongly linked to the correct activation and balancing of the maternal immune system. Besides abortion as possible result of improper early pregnancy development, other pregnancy associated conditions like preeclampsia (PE), intrauterine growth retardation (IUGR), preterm labour, or gestational diabetes mellitus (GDM) are linked to immunologic overactivation and dysregulation. Both the innate and the adaptive immune system, and therefore B and T lymphocytes, natural killer cells (NK), macrophages and dendritic cells (DCs) are all involved in trophoblast invasion, pregnancy maintenance, and development of pregnancy disorders. Peroxisome proliferator activated receptors (PPARs) are nuclear transcription factors with three known isotypes: PPAR , PPARβ/δ, and PPARγ. They are expressed in most human organs and their function extends from regulating metabolism, homeostasis, and carcinogenesis to immune response. In the recent years, PPARs have been identified in most reproductive tissues and in all lines of immune cells. Only in few cases, the role of PPARs in reproductive immunology has been elucidated though the role of PPARs in immune answer and immunotolerance is evident. Within this paper we would like to give an update on today’s knowledge about PPARs and immune cells in reproduction and highlight interesting interferences in regard of future therapeutic targets. 1. Introduction Trophoblast invasion at the beginning of pregnancy development is often described in the context of pregnancy complications. The underlying pathophysiology includes elevated macrophage populations hampering trophoblast invasion and inducing trophoblast apoptosis [1, 2]. As another, even bigger part of the innate immune response decidual natural killer (dNK) cells have been identified in promoting trophoblast invasion [3] and reduced numbers of dNK have been reported associated with IUGR [4]. The components of the adaptive immune system present at the fetomaternal interface as the site of immunologic tolerance plays an important role in balancing the maternal immune response to the fetal allograft. For many years a simplified approach to this complex process of immunotolerance was postulated. Thus pregnancy was regarded as a phenomenon of T helper cells subgroup 2 (Th2) going along with inhibition of T helper cells subgroup 1 (Th1) and their cytotoxic effects [5]. However the results of the last years have shown that cytokines associated with Th1 are closely linked to a positive pregnancy outcome [6]. Besides this
References
[1]
S. J. Renaud, L. M. Postovit, S. K. Macdonald-Goodfellow, G. T. McDonald, J. D. Caldwell, and C. H. Graham, “Activated macrophages inhibit human cytotrophoblast invasiveness in vitro,” Biology of Reproduction, vol. 73, no. 2, pp. 237–243, 2005.
[2]
F. Reister, H. G. Frank, J. C. P. Kingdom et al., “Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women,” Laboratory Investigation, vol. 81, no. 8, pp. 1143–1152, 2001.
[3]
S. E. Hiby, J. J. Walker, K. M. O'Shaughnessy et al., “Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success,” Journal of Experimental Medicine, vol. 200, no. 8, pp. 957–965, 2004.
[4]
P. J. Williams, J. N. Bulmer, R. F. Searle, B. A. Innes, and S. C. Robson, “Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: a comparison with late normal pregnancy,” Reproduction, vol. 138, no. 1, pp. 177–184, 2009.
[5]
T. G. Wegmann, H. Lin, L. Guilbert, and T. R. Mosmann, “Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?” Immunology Today, vol. 14, no. 7, pp. 353–356, 1993.
[6]
S. A. McCracken, E. Gallery, and J. M. Morris, “Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success,” The Journal of Immunology, vol. 172, no. 7, pp. 4583–4591, 2004.
[7]
Y. Sasaki, D. Darmochwal-Kolarz, D. Suzuki et al., “Proportion of peripheral blood and decidual CD4+ regulatory T cells in pre-eclampsia,” Clinical and Experimental Immunology, vol. 149, no. 1, pp. 139–145, 2007.
[8]
T. Tilburgs, D. L. Roelen, B. J. Van Der Mast et al., “Evidence for a selective migration of fetus-specific CD4+ regulatory T cells from the peripheral blood to the decidua in human pregnancy,” The Journal of Immunology, vol. 180, no. 8, pp. 5737–5745, 2008.
[9]
S. Guenther, T. Vrekoussis, S. Heublein et al., “Decidual macrophages are significantly increased in spontaneous miscarriages and over-express fasL: a potential role for macrophages in trophoblast apoptosis,” International Journal of Molecular Sciences, vol. 13, no. 7, pp. 9069–9080, 2012.
[10]
R. K. Semple, V. K. K. Chatterjee, and S. O'Rahilly, “PPARγ and human metabolic disease,” The Journal of Clinical Investigation, vol. 116, no. 3, pp. 581–589, 2006.
[11]
S. Yu and J. K. Reddy, “Transcription coactivators for peroxisome proliferator-activated receptors,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 936–951, 2007.
[12]
S. W. Beaven and P. Tontonoz, “Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia,” Annual Review of Medicine, vol. 57, pp. 313–329, 2006.
[13]
G. Chinetti, J. C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation,” Inflammation Research, vol. 49, no. 10, pp. 497–505, 2000.
[14]
T. J. Standiford, V. G. Keshamouni, and R. C. Reddy, “Peroxisome proliferator-activated receptor-{gamma} as a regulator of lung inflammation and repair,” Proceedings of the American Thoracic Society, vol. 2, pp. 226–231, 2005.
[15]
L. Michalik, B. Desvergne, C. Dreyer, M. Gavillet, R. N. Laurini, and W. Wahli, “PPAR expression and function during vertebrate development,” International Journal of Developmental Biology, vol. 46, no. 1, pp. 105–114, 2002.
[16]
M. Lappas and G. E. Rice, “Transcriptional regulation of the processes of human labour and delivery,” Placenta, vol. 30, supplement, pp. 90–95, 2009.
[17]
S. J. Holdsworth-Carson, R. Lim, A. Mitton et al., “Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia,” Placenta, vol. 31, no. 3, pp. 222–229, 2010.
[18]
A. Tarrade, K. Schoonjans, L. Pavan et al., “PPARγ/RXRα heterodimers control human trophoblast invasion,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 5017–5024, 2001.
[19]
N. Martínez, M. Kurtz, E. Capobianco, R. Higa, V. White, and A. Jawerbaum, “PPARα agonists regulate lipid metabolism and nitric oxide production and prevent placental overgrowth in term placentas from diabetic rats,” Journal of Molecular Endocrinology, vol. 47, no. 1, pp. 1–12, 2011.
[20]
H. Wang, H. Xie, X. Sun et al., “Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor δ signaling is critical to pregnancy success,” The Journal of Biological Chemistry, vol. 282, no. 52, pp. 37770–37782, 2007.
[21]
A. Tarrade, K. Schoonjans, L. Pavan et al., “PPARγ/RXRα heterodimers control human trophoblast invasion,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 5017–5024, 2001.
[22]
B. Rauwel, B. Mariamé, H. Martin 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,” Journal of Virology, vol. 84, no. 6, pp. 2946–2954, 2010.
[23]
R. Belfort, R. Berria, J. Cornell, and K. Cusi, “Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 2, pp. 829–836, 2010.
[24]
P. Lefebvre, G. Chinetti, J. C. Fruchart, and B. Staels, “Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis,” The Journal of Clinical Investigation, vol. 116, pp. 571–580, 2006.
[25]
Q. Wang, H. Fujii, and G. T. Knipp, “Expression of PPAR and RXR isoforms in the developing rat and human term placentas,” Placenta, vol. 23, no. 8-9, pp. 661–671, 2002.
[26]
N. Martínez, M. Kurtz, E. Capobianco, R. Higa, V. White, and A. Jawerbaum, “PPARα agonists regulate lipid metabolism and nitric oxide production and prevent placental overgrowth in term placentas from diabetic rats,” Journal of Molecular Endocrinology, vol. 47, no. 1, pp. 1–12, 2011.
[27]
L. G. Mikael, J. Pancer, Q. Wu, and R. Rozen, “Disturbed one-carbon metabolism causing adverse reproductive outcomes in mice is associated with altered expression of apolipoprotein AI and inflammatory mediators PPARα, interferon-γ, and interleukin-10,” Journal of Nutrition, vol. 142, no. 3, pp. 411–418, 2012.
[28]
A. Yessoufou, A. Hichami, P. Besnard, K. Moutairou, and N. A. Khan, “Peroxisome proliferator-activated receptor α deficiency increases the risk of maternal abortion and neonatal mortality in murine pregnancy with or without diabetes mellitus: modulation of T cell differentiation,” Endocrinology, vol. 147, no. 9, pp. 4410–4418, 2006.
[29]
R. Mukherjee, L. Jow, G. E. Croston, and J. R. Paterniti, “Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARγ2 versus PPARγ1 and activation with retinoid X receptor agonists and antagonists,” The Journal of Biological Chemistry, vol. 272, no. 12, pp. 8071–8076, 1997.
[30]
H. Wang, H. Xie, X. Sun et al., “Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor δ signaling is critical to pregnancy success,” The Journal of Biological Chemistry, vol. 282, no. 52, pp. 37770–37782, 2007.
[31]
Y. Barak, D. Liao, W. He et al., “Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 1, pp. 303–308, 2002.
[32]
L. Julan, H. Guan, J. P. Van Beek, and K. Yang, “Peroxisome proliferator-activated receptor δ suppresses 11β-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells,” Endocrinology, vol. 146, no. 3, pp. 1482–1490, 2005.
[33]
S. E. Dunn, R. Bhat, D. S. Straus et al., “Peroxisome proliferator-activated receptor δ limits the expansion of pathogenic Th cells during central nervous system autoimmunity,” Journal of Experimental Medicine, vol. 207, no. 8, pp. 1599–1608, 2010.
[34]
B. Toth, M. Bastug, C. Scholz et al., “Leptin and peroxisome proliferator-activated receptors: impact on normal and disturbed first trimester human pregnancy,” Histology and Histopathology, vol. 23, no. 12, pp. 1465–1475, 2008.
[35]
W. T. Schaiff, F. F. Knapp, Y. Barak, T. Biron-Shental, D. M. Nelson, and Y. Sadovsky, “Ligand-activated peroxisome proliferator activated receptor γ alters placental morphology and placental fatty acid uptake in mice,” Endocrinology, vol. 148, no. 8, pp. 3625–3634, 2007.
[36]
A. Tarrade, K. Schoonjans, L. Pavan et al., “PPARγ/RXRα heterodimers control human trophoblast invasion,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 5017–5024, 2001.
[37]
F. P. McCarthy, S. Drewlo, J. Kingdom, E. J. Johns, S. K. Walsh, and L. C. Kenny, “Peroxisome proliferator-activated receptor-γ as a potential therapeutic target in the treatment of preeclampsia,” Hypertension, vol. 58, no. 2, pp. 280–286, 2011.
[38]
M. E. Street, P. Seghini, S. Feini et al., “Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls,” European Journal of Endocrinology, vol. 155, no. 4, pp. 567–574, 2006.
[39]
M. Desai, Guang Han, M. Ferelli, N. Kallichanda, and R. H. Lane, “Programmed upregulation of adipogenic transcription factors in intrauterine growth-restricted offspring,” Reproductive Sciences, vol. 15, no. 8, pp. 785–796, 2008.
[40]
W. T. Schaiff, I. Bildirici, M. Cheong, P. L. Chern, D. M. Nelson, and Y. Sadovsky, “Peroxisome proliferator-activated receptor-γ and retinoid X receptor signaling regulate fatty acid uptake by primary human placental Trophoblasts,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 7, pp. 4267–4275, 2005.
[41]
F. P. McCarthy, S. Drewlo, F. A. English et al., “Evidence implicating peroxisome proliferator-activated receptor-γ in the pathogenesis of preeclampsia,” Hypertension, vol. 58, no. 5, pp. 882–887, 2011.
[42]
M. Lappas, M. Permezel, H. M. Georgiou, and G. E. Rice, “Regulation of proinflammatory cytokines in human gestational tissues by peroxisome proliferator-activated receptor-γ: effect of 15-deoxy-δ12,14-PGJ2 and troglitazone,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 10, pp. 4667–4672, 2002.
[43]
D. Vats, L. Mukundan, J. I. Odegaard et al., “Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation,” Cell Metabolism, vol. 4, no. 1, pp. 13–24, 2006.
[44]
J. I. Odegaard, R. R. Ricardo-Gonzalez, M. H. Goforth et al., “Macrophage-specific PPARγ controls alternative activation and improves insulin resistance,” Nature, vol. 447, no. 7148, pp. 1116–1120, 2007.
[45]
T. Nagamatsu and D. J. Schust, “The contribution of macrophages to normal and pathological pregnancies,” American Journal of Reproductive Immunology, vol. 63, no. 6, pp. 460–471, 2010.
[46]
F. Porcheray, S. Viaud, A. C. Rimaniol et al., “Macrophage activation switching: an asset for the resolution of inflammation,” Clinical and Experimental Immunology, vol. 142, no. 3, pp. 481–489, 2005.
[47]
F. O. Martinez, L. Helming, and S. Gordon, “Alternative activation of macrophages: an immunologic functional perspective,” Annual Review of Immunology, vol. 27, pp. 451–483, 2009.
[48]
M. Ricote, J. S. Welch, and C. K. Glass, “Regulation of macrophage gene expression by the peroxisome proliferator-activated receptor-γ,” Hormone Research, vol. 54, no. 5-6, pp. 275–280, 2000.
[49]
A. Chawla, “Control of macrophage activation and function by PPARs,” Circulation Research, vol. 106, no. 10, pp. 1559–1569, 2010.
[50]
M. A. Bouhlel, B. Derudas, E. Rigamonti et al., “PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties,” Cell Metabolism, vol. 6, no. 2, pp. 137–143, 2007.
[51]
G. Chinetti, J. C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors: new targets for the pharmacological modulation of macrophage gene expression and function,” Current Opinion in Lipidology, vol. 14, no. 5, pp. 459–468, 2003.
[52]
A. Sica and A. Mantovani, “Macrophage plasticity and polarization: in vivo veritas,” The Journal of Clinical Investigation, vol. 122, no. 3, pp. 787–795, 2012.
[53]
L. Mukundan, J. I. Odegaard, C. R. Morel et al., “PPAR-Δ senses and orchestrates clearance of apoptotic cells to promote tolerance,” Nature Medicine, vol. 15, no. 11, pp. 1266–1272, 2009.
[54]
M. Dong, J. He, Z. Wang, X. Xie, and H. Wang, “Placental imbalance of Th1- and Th2-type cytokines in preeclampsia,” Acta Obstetricia et Gynecologica Scandinavica, vol. 84, no. 8, pp. 788–793, 2005.
[55]
S. Banerjee, A. Smallwood, J. Moorhead et al., “Placental expression of interferon-γ (IFN-γ) and its receptor IFN-γR2 fail to switch from early hypoxic to late normotensive development in preeclampsia,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 2, pp. 944–952, 2005.
[56]
J. Szekeres-Bartho, M. Halasz, and T. Palkovics, “Progesterone in pregnancy; receptor-ligand interaction and signaling pathways,” Journal of Reproductive Immunology, vol. 83, no. 1-2, pp. 60–64, 2009.
[57]
S. E. Dunn, R. Bhat, D. S. Straus et al., “Peroxisome proliferator-activated receptor δ limits the expansion of pathogenic Th cells during central nervous system autoimmunity,” Journal of Experimental Medicine, vol. 207, no. 8, pp. 1599–1608, 2010.
[58]
T. M. Lindstr？m and P. R. Bennett, “15-Deoxy-Δ12, 14-prostaglandin J2 inhibits interleukin-1β-induced nuclear factor-κB in human amnion and myometrial cells: mechanisms and implications,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 6, pp. 3534–3543, 2005.
[59]
D. Chiron, I. Bekeredjian-Ding, C. Pellat-Deceunynck, R. Bataille, and G. Jego, “Toll-like receptors: lessons to learn from normal and malignant human B cells,” Blood, vol. 112, no. 6, pp. 2205–2213, 2008.
[60]
J. Carbone, A. Gallego, N. Lanio et al., “Quantitative abnormalities of peripheral blood distinct T, B, and natural killer cell subsets and clinical findings in obstetric antiphospholipid syndrome,” Journal of Rheumatology, vol. 36, no. 6, pp. 1217–1225, 2009.
[61]
C. C. Zhou, S. Ahmad, T. Mi et al., “Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling,” Hypertension, vol. 51, no. 4, pp. 1010–1019, 2008.
[62]
B. Lamarca, K. Wallace, F. Herse et al., “Hypertension in response to placental ischemia during pregnancy: role of B lymphocytes,” Hypertension, vol. 57, no. 4, pp. 865–871, 2011.
[63]
D. M. Ray, F. Akbiyik, S. H. Bernstein, and R. P. Phipps, “CD40 engagement prevents peroxisome proliferator-activated receptor γ agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-κB-dependent mechanism,” The Journal of Immunology, vol. 174, no. 7, pp. 4060–4069, 2005.
[64]
T. M. Garcia-Bates, C. J. Baglole, M. P. Bernard, T. I. Murant, P. J. Simpson-Haidaris, and R. P. Phipps, “Peroxisome proliferator-activated receptor γ ligands enhance human B cell antibody production and differentiation,” The Journal of Immunology, vol. 183, no. 11, pp. 6903–6912, 2009.
[65]
J. Zhang, Z. Chen, G. N. Smith, and B. A. Croy, “Natural killer cell-triggered vascular transformation: maternal care before birth?” Cellular and Molecular Immunology, vol. 8, no. 1, pp. 1–11, 2011.
[66]
P. Vacca, C. Cantoni, M. Vitale et al., “Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 26, pp. 11918–11923, 2010.
[67]
Y. Lin, Y. Zhong, W. Shen et al., “TSLP-induced placental DC activation and IL-10+ NK cell expansion: comparative study based on BALB/c × C57BL/6 and NOD/SCID × C57BL/6 pregnant models,” Clinical Immunology, vol. 126, no. 1, pp. 104–117, 2008.
[68]
I. T. González, G. Barrientos, N. Freitag et al., “Uterine NK cells are critical in shaping DC immunogenic functions compatible with pregnancy progression,” PLoS One, vol. 7, no. 10, Article ID e46755, 2012.
[69]
A. R. French and W. M. Yokoyama, “Natural killer cells and viral infections,” Current Opinion in Immunology, vol. 15, no. 1, pp. 45–51, 2003.
[70]
X. Zhang, M. C. Rodriguez-Galán, J. J. Subleski et al., “Peroxisome proliferator-activated receptor-γ and its ligands attenuate biologic functions of human natural killer cells,” Blood, vol. 104, no. 10, pp. 3276–3284, 2004.
[71]
P. Gosset, A.-S. Charbonnier, P. Delerive, et al., “Peroxisome proliferator-activated receptor γ activators affect the maturation of human monocyte-derived dendritic cells,” European Journal of Immunology, vol. 31, no. 10, pp. 2857–2865, 2001.
[72]
A. Nencioni, F. Grünebach, A. Zobywlaski, C. Denzlinger, W. Brugger, and P. Brossart, “Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor γ,” The Journal of Immunology, vol. 169, no. 3, pp. 1228–1235, 2002.
[73]
G. Desoye and S. Hauguel-De Mouzon, “The human placenta in gestational diabetes mellitus: the insulin and cytokine network,” Diabetes Care, vol. 30, no. 2, pp. S120–S126, 2007.
[74]
B. Huppertz, “Placental origins of preeclampsia: challenging the current hypothesis,” Hypertension, vol. 51, no. 4, pp. 970–975, 2008.
[75]
M. F. Chammas, T. M. Nguyen, M. A. Li, B. S. Nuwayhid, and L. C. Castro, “Expectant management of severe preterm preeclampsia: is intrauterine growth restriction an indication for immediate delivery?” American Journal of Obstetrics and Gynecology, vol. 183, no. 4, pp. 853–858, 2000.
[76]
J. J. Walker, “Pre-eclampsia,” The Lancet, vol. 356, no. 9237, pp. 1260–1265, 2000.
[77]
L. A. Barbour, C. E. McCurdy, T. L. Hernandez, J. P. Kirwan, P. M. Catalano, and J. E. Friedman, “Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes,” Diabetes Care, vol. 30, supplement 2, pp. S112–S119, 2007.
[78]
A. Hawfield and B. I. Freedman, “Pre-eclampsia: the pivotal role of the placenta in its pathophysiology and markers for early detection,” Therapeutic Advances in Cardiovascular Disease, vol. 3, no. 1, pp. 65–73, 2009.
[79]
J. S. Gilbert, M. J. Ryan, B. B. Lamarca, M. Sedeek, S. R. Murphy, and J. P. Granger, “Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction,” American Journal of Physiology, vol. 294, no. 2, pp. H541–H550, 2008.
[80]
A. Jawerbaum, E. Capobianco, C. Pustovrh et al., “Influence of peroxisome proliferator-activated receptor γ activation by its endogenous ligand 15-deoxy Δ 1214 prostaglandin J2 on nitric oxide production in term placental tissues from diabetic women,” Molecular Human Reproduction, vol. 10, no. 9, pp. 671–676, 2004.
[81]
M. Lappas, M. Permezel, and G. E. Rice, “Release of proinflammatory cytokines and 8-isoprostane from placenta, adipose tissue, and skeletal muscle from normal pregnant women and women with gestational diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 11, pp. 5627–5633, 2004.
[82]
L. Sykes, D. A. MacIntyre, X. J. Yap, S. Ponnampalam, T. G. Teoh, and P. R. Bennett, “Changes in the Th1:Th2 cytokine bias in pregnancy and the effects of the anti-inflammatory cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2,” Mediators of Inflammation, vol. 2012, Article ID 416739, 12 pages, 2012.
[83]
W. T. Schaiff, Y. Barak, and Y. Sadovsky, “The pleiotropic function of PPARγ in the placenta,” Molecular and Cellular Endocrinology, vol. 249, no. 1-2, pp. 10–15, 2006.
[84]
H. Martin, “Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components,” Mutation Research, vol. 669, no. 1-2, pp. 1–7, 2009.
