Leptin does not Induce an Inflammatory Response in the Murine Placenta

Abstract

Leptin is described as a pro-inflammatory signal in fat tissue, which is released from adipocytes and in turn activates immune cells. Also, leptin levels are known to be increased in pregnancies complicated with enhanced inflammatory processes in the placenta. Hence, we assumed that increased leptin amounts might contribute to inducing an inflammatory response in the placenta. To test this hypothesis, pregnant mice were continuously infused with recombinant murine leptin s. c. from day g13 to g16, resulting in a 3-fold increase of maternal circulating serum leptin levels. Dissected placentas were examined for the expression of pro-inflammatory cytokines IL-6 and TNF-alpha and the anti-inflammatory cytokine IL-10 using qPCR analysis. No changes were found except for TNF-alpha, which was slightly elevated upon leptin stimulation. However, TNF-alpha protein levels were not significantly higher in placentas from leptin treated mice. Also, leukocyte infiltration in the labyrinth section of placentas was not increased. In summary, our data demonstrate for the first time that elevated leptin levels alone do not induce an inflammatory response in the placenta.

Key words

placenta - inflammation - leptin

^* These authors contributed equally to this work.

• References

• 1 Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382: 250-252
• 2 Cinti S, Frederich RC, Zingaretti MC, De Matteis R, Flier JS, Lowell BB. Immunohistochemical localization of leptin and uncoupling protein in white and brown adipose tissue. Endocrinology 1997; 138: 797-804
• 3 Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y. Correlation between soluble endoglin, vascular endothelial growth factor receptor-1, and adipocytokines in preeclampsia. J Clin Endocrinol Metab 2007; 92: 2672-2679
• 4 Niswender KD, Schwartz MW. Insulin and leptin revisited: adi­posity signals with overlapping physiological and intracellular signaling capabilities. Front Neuroendocrinol 2003; 24: 1-10
• 5 La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol 2004; 4: 371-379
• 6 Bowen JM, Chamley L, Mitchell MD, Keelan JA. Cytokines of the placenta and extra-placental membranes: biosynthesis, secretion and roles in establishment of pregnancy in women. Placenta 2002; 23: 239-256
• 7 Challier JC, Basu S, Bintein T, Minium J, Hotmire K, Catalano PM, Hauguel-de Mouzon S. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 2008; 29: 274-281
• 8 Radaelli T, Varastehpour A, Catalano P, Hauguel-de Mouzon S. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes 2003; 52: 2951-2958
• 9 Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia. Semin Immunopathol 2007; 29: 151-162
• 10 Enquobahrie DA, Meller M, Rice K, Psaty BM, Siscovick DS, Williams MA. Differential placental gene expression in preeclampsia. Am J Obstet Gynecol 2008; 199: 566-e561–e511
• 11 Dotsch J, Nusken KD, Knerr I, Kirschbaum M, Repp R, Rascher W. Leptin and neuropeptide Y gene expression in human placenta: ontogeny and evidence for similarities to hypothalamic regulation. J Clin Endocrinol Metab 1999; 84: 2755-2758
• 12 Hendler I, Blackwell SC, Mehta SH, Whitty JE, Russell E, Sorokin Y, Cotton DB. The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. Am J Obstet Gynecol 2005; 193: 979-983
• 13 Cameo P, Bischof P, Calvo JC. Effect of leptin on progesterone, human chorionic gonadotropin, and interleukin-6 secretion by human term trophoblast cells in culture. Biol Reprod 2003; 68: 472-477
• 14 Rother E, Kuschewski R, Alcazar MA, Oberthuer A, Bae-Gartz I, Vohlen C, Roth B, Dotsch J. Hypothalamic JNK1 and IKKbeta activation and impaired early postnatal glucose metabolism after maternal perinatal high-fat feeding. Endocrinology 2012; 153: 770-781
• 15 Hegen M, Gaestel M, Nickerson-Nutter CL, Lin LL, Telliez JB. MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J Immunol 2006; 177: 1913-1917
• 16 Yang J, Rosen SD, Bendele P, Hemmerich S. Induction of PNAd and N-acetylglucosamine 6-O-sulfotransferases 1 and 2 in mouse collagen-induced arthritis. BMC Immunol 2006; 7: 12
• 17 Sucak A, Kanat-Pektas M, Gungor T, Mollamahmutoglu L. Leptin levels and antihypertensive treatment in preeclampsia. Singapore Med J 2010; 51: 39-43
• 18 Anim-Nyame N, Sooranna SR, Steer PJ, Johnson MR. Longitudinal analysis of maternal plasma leptin concentrations during normal pregnancy and pre-eclampsia. Hum Reprod 2000; 15: 2033-2036
• 19 Mumtaz F, Memon AR, Yousfani S, Tahir SM, Khushk I, Memon M, Memon A. Role of serum leptin level as a marker of severity of pre eclampsia. J Ayub Med Coll Abbottabad 2008; 20: 13-15
• 20 Ramsay JE, Ferrell WR, Crawford L, Wallace AM, Greer IA, Sattar N. Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. J Clin Endocrinol Metab 2002; 87: 4231-4237
• 21 Castellucci M, De Matteis R, Meisser A, Cancello R, Monsurro V, Islami D, Sarzani R, Marzioni D, Cinti S, Bischof P. Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Mol Hum Reprod 2000; 6: 951-958
• 22 Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor. OB-R. Cell 1995; 83: 1263-1271
• 23 Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996; 12: 318-320
• 24 Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverini PJ, Flores-Riveros JR. Biological action of leptin as an angiogenic factor. Science 1998; 281: 1683-1686
• 25 Jansson N, Greenwood SL, Johansson BR, Powell TL, Jansson T. Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. J Clin Endocrinol Metab 2003; 88: 1205-1211
• 26 Bowen RS, Gu Y, Zhang Y, Lewis DF, Wang Y. Hypoxia promotes interleukin-6 and -8 but reduces interleukin-10 production by placental trophoblast cells from preeclamptic pregnancies. J Soc Gynecol Investig 2005; 12: 428-432
• 27 McDonald EA, Kurtis JD, Acosta L, Gundogan F, Sharma S, Pond-Tor S, Wu HW, Friedman JF. Schistosome egg antigens elicit a proinflammatory response by trophoblast cells of the human placenta. Infect Immun 2013; 81: 704-712
• 28 Noyola-Martinez N, Diaz L, Avila E, Halhali A, Larrea F, Barrera D. Calcitriol downregulates TNF-alpha and IL-6 expression in cultured placental cells from preeclamptic women. Cytokine 2013; 61: 245-250
• 29 Klaffenbach D, Meissner U, Raake M, Fahlbusch F, Alejandre Alcazar MA, Allabauer I, Kratzsch J, Rascher W, Dotsch J. Upregulation of leptin-receptor in placental cells by hypoxia. Regul Pept 2011; 167: 156-162
• 30 Schulz LC, Widmaier EP, Qiu J, Roberts RM. Effect of leptin on mouse trophoblast giant cells. Biol Reprod 2009; 80: 415-424
• 31 Schulz LC, Widmaier EP. The effect of leptin on mouse trophoblast cell invasion. Biol Reprod 2004; 71: 1963-1967