Lipopolysaccharide Appears to Activate Human Endometrial Endothelial Cells Through TLR-4-dependent and TLR-4-independent Mechanisms

Overview

Journal Am J Reprod Immunol

Specialties Allergy & Immunology
Reproductive Medicine

Date 2012 Jun 8

PMID 22672000

Citations 19

Authors

Graciela Krikun

Jordan Trezza

Jeff Shaw

Mizan Rahman

Seth Guller

Vikki M Abrahams

Charles J Lockwood

Affiliations

Soon will be listed here.

Abstract

Problem: Uterine innate immunity remains poorly characterized, and while endometrial endothelial cells are known to express Toll-like receptors (TLRs), little is known about their function in these cells. The present study evaluated the effect of Gram-negative bacterial lipopolysaccharide (LPS) on human endometrial endothelial cell (HEECs) cytokine secretion and tissue factor expression, and the role of TLR-4 in these responses.

Methods: Human endometrial endothelial cells were treated with or without LPS ± LPS-RS, a TLR-4 antagonist, via the binding of MD-2. After 24 hr, cell-free supernatants were evaluated for cytokines by multiplex analysis and cell lysates were analyzed for tissue factor expression by Western blot.

Results: Treatment of HEECs with LPS significantly upregulated the secretion of IL-6, IL-8, and G-CSF, and this was prevented by LPS-RS. LPS also induced tissue factor expression by the HEECs; however, this was unaffected by LPS-RS.

Conclusion: These findings suggest that TLR-4 is functional in HEECs and its activation by bacterial LPS induces a specific cytokine/chemokine response. However, bacterial LPS also induced tissue factor expression in what seemed to be a TLR-4-independent fashion, suggesting that this bacterial component can act on the HEECs through TLR-4-dependent and TLR-4-independent pathways. These findings indicate that endometrial endothelial cells may play an active role in uterine innate immunity.

Citing Articles

Biosynthetic pathway for leukotrienes is stimulated by lipopolysaccharide and cytokines in pig endometrial stromal cells.

Jana B, Andronowska A, Calka J, Mowinska A Sci Rep. 2025; 15(1):2806.

PMID: 39843578 PMC: 11754892. DOI: 10.1038/s41598-025-86787-1.

Noradrenaline and Adrenoreceptors Are Involved in the Regulation of Prostaglandin I2 Production in the Porcine Endometrium after Experimentally Induced Inflammation.

Jana B, Calka J, Andronowska A, Mowinska A, Witek K, Palus K Int J Mol Sci. 2024; 25(12).

PMID: 38928020 PMC: 11204358. DOI: 10.3390/ijms25126313.

Mesenchymal Stem Cells Suppress Inflammatory Cytokines in Lipopolysaccharide Exposed Preterm and Term Human Pregnant Myometrial Cells.

Mani A, Hotra J, Blackwell S, Goetzl L, Refuerzo J AJP Rep. 2024; 14(1):e69-e73.

PMID: 38370325 PMC: 10874693. DOI: 10.1055/a-2216-9194.

Toll-like Receptors as Pro-Thrombotic Drivers in Viral Infections: A Narrative Review.

Panzer B, Kopp C, Neumayer C, Koppensteiner R, Jozkowicz A, Poledniczek M Cells. 2023; 12(14).

PMID: 37508529 PMC: 10377790. DOI: 10.3390/cells12141865.

ATP Induces Interleukin-8, Intracellular Calcium Release, and ERK1/2 Phosphorylation in Bovine Endometrial Cells, Partially through P2Y Receptors.

Gutierrez N, Teuber S, Alarcon P, Burgos R, Hidalgo M Animals (Basel). 2023; 13(5).

PMID: 36899697 PMC: 10000103. DOI: 10.3390/ani13050841.

References

Colucci M, Balconi G, Lorenzet R, Pietra A, Locati D, Donati M . Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest. 1983; 71(6):1893-6. PMC: 370395. DOI: 10.1172/jci110945. View

Michels T . Chronic endometritis. Am Fam Physician. 1995; 52(1):217-22. View

Faure E, Equils O, Sieling P, Thomas L, Zhang F, Kirschning C . Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem. 2001; 275(15):11058-63. DOI: 10.1074/jbc.275.15.11058. View

Satta N, Kruithof E, Reber G, Moerloose P . Induction of TLR2 expression by inflammatory stimuli is required for endothelial cell responses to lipopeptides. Mol Immunol. 2008; 46(1):145-57. DOI: 10.1016/j.molimm.2008.07.017. View

Romero R, Espinoza J, Goncalves L, Kusanovic J, Friel L, Hassan S . The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007; 25(1):21-39. PMC: 8324073. DOI: 10.1055/s-2006-956773. View

Krikun G, Mor G, Huang J, Schatz F, Lockwood C . Metalloproteinase expression by control and telomerase immortalized human endometrial endothelial cells. Histol Histopathol. 2005; 20(3):719-24. DOI: 10.14670/HH-20.719. View

Faure E, Thomas L, Xu H, Medvedev A, Equils O, Arditi M . Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol. 2001; 166(3):2018-24. DOI: 10.4049/jimmunol.166.3.2018. View

Witlin A, Sibai B . Postpartum ovarian vein thrombosis after vaginal delivery: a report of 11 cases. Obstet Gynecol. 1995; 85(5 Pt 1):775-80. DOI: 10.1016/0029-7844(95)00040-x. View

Krikun G, Lockwood C, Abrahams V, Mor G, Paidas M, Guller S . Expression of Toll-like receptors in the human decidua. Histol Histopathol. 2007; 22(8):847-54. DOI: 10.14670/HH-22.847. View

10.

Akira S, Takeda K . Toll-like receptor signalling. Nat Rev Immunol. 2004; 4(7):499-511. DOI: 10.1038/nri1391. View

11.

Aflatoonian R, Fazeli A . Toll-like receptors in female reproductive tract and their menstrual cycle dependent expression. J Reprod Immunol. 2007; 77(1):7-13. DOI: 10.1016/j.jri.2007.03.014. View

12.

Pierangeli S, Vega-Ostertag M, Raschi E, Liu X, Romay-Penabad Z, De Micheli V . Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis. 2007; 66(10):1327-33. PMC: 1994302. DOI: 10.1136/ard.2006.065037. View

13.

Oude Nijhuis C, Vellenga E, Daenen S, Kamps W, de Bont E . Endothelial cells are main producers of interleukin 8 through Toll-like receptor 2 and 4 signaling during bacterial infection in leukopenic cancer patients. Clin Diagn Lab Immunol. 2003; 10(4):558-63. PMC: 164273. DOI: 10.1128/cdli.10.4.558-563.2003. View

14.

Wira C, Grant-Tschudy K, Crane-Godreau M . Epithelial cells in the female reproductive tract: a central role as sentinels of immune protection. Am J Reprod Immunol. 2005; 53(2):65-76. DOI: 10.1111/j.1600-0897.2004.00248.x. View

15.

Pellati D, Mylonakis I, Bertoloni G, Fiore C, Andrisani A, Ambrosini G . Genital tract infections and infertility. Eur J Obstet Gynecol Reprod Biol. 2008; 140(1):3-11. DOI: 10.1016/j.ejogrb.2008.03.009. View

16.

Magder S, Neculcea J, Neculcea V, Sladek R . Lipopolysaccharide and TNF-alpha produce very similar changes in gene expression in human endothelial cells. J Vasc Res. 2006; 43(5):447-61. DOI: 10.1159/000095162. View

17.

Chirinos J, Garcia J, Alcaide M, Toledo G, Baracco G, Lichtstein D . Septic thrombophlebitis: diagnosis and management. Am J Cardiovasc Drugs. 2006; 6(1):9-14. DOI: 10.2165/00129784-200606010-00002. View

18.

Nagyoszi P, Wilhelm I, Farkas A, Fazakas C, Dung N, Hasko J . Expression and regulation of toll-like receptors in cerebral endothelial cells. Neurochem Int. 2010; 57(5):556-64. DOI: 10.1016/j.neuint.2010.07.002. View

19.

Cromer W, Mathis J, Granger D, Chaitanya G, Alexander J . Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol. 2011; 17(5):578-93. PMC: 3040330. DOI: 10.3748/wjg.v17.i5.578. View

20.

Cakmak H, Schatz F, Huang S, Buchwalder L, Rahman M, Arici A . Progestin suppresses thrombin- and interleukin-1beta-induced interleukin-11 production in term decidual cells: implications for preterm delivery. J Clin Endocrinol Metab. 2005; 90(9):5279-86. DOI: 10.1210/jc.2005-0210. View