Role of progesterone in TLR4-MyD88-dependent signaling pathway in pre-eclampsia

Abstract

The role of progesterone in the Toll-like receptor 4 (TLR4)-MyD88-dependent signaling pathway in pre-eclampsia was studied. Peripheral blood mononuclear cells (PBMCs) from pre-eclampsia (PE) patients were subjected to primary culture, and stimulated with different concentrations of progesterone (0, 10⁻⁸, 10⁻⁶, and 10⁻⁴ mol/L). The mRNA expression of TLR4, MyD88 and nuclear factor-kappaB (NF-κB) was detected by using real-time PCR. The Ikappa-B protein expression was detected by using Western blotting. The expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the supernatant was determined by using ELISA. With the concentrations of progesterone increasing, the mRNA expression levels of TLR4, MyD88 and NF-κB in 2^−ΔΔCT value were significantly decreased, and the IkappaB protein expression levels were significantly increased. The TNF-α and IL-6 expression showed a downward trend when the progesterone concentration increased, and there were significant differences among all of the groups (P<0.05). It was suggested that progesterone can inhibit the TLR4-MyD88-dependent signaling pathway in PE significantly and benefit for the pregnancy.

Keywords

progesterone / pre-eclampsia / Toll-like receptor 4 / tumor necrosis factor-α / nuclear factor-κB / Ikappa-B / interleukin-6

References

[1] MyattL. Role of placenta in preeclampsia. Endocrine, 2002, 19(1): 103-111

[2] KimYM, RomeroR, OhSY, et al.. Toll-like receptor 4: a potential link between “danger signals”, the innate immune system, and pre-eclampsia. Am J Obstet Gynecol, 2005, 193(32): 921-927

[3] AbrahamsVM, VisintinI, AldoPB, et al.. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. Immunol, 2005, 175(12): 8096-8104

[4] AbramhenVM, Bole-aldoYMKIM, et al.. Divergent trophoblast responses to bacterial products mediated by TLRs. Immune, 2004, 17(3): 4286-4296

[5] MedzhitovR, JanewayCAJr. Decoding the patterns of self and nonself by the innate immune system. Science, 2002, 296(5566): 298-300

[6] AkiraS, TakedaK, KaishoT. Toll-like receptors, critical proteins linking innate and acquired immunity. Nat Immunol, 2001, 2(8): 675-680

[7] O’NeillLA. The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence. Biochem Soc Trans, 2000, 28(5): 557-563

[8] FaureE, EquilsO, SielingPA, et al.. 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. Biol Chem, 2000, 275(15): 11 058-11 063

[9] ChenG, ShiJ, JinW, et al.. Progesterone administration modulates TLRs/NF-kappaB signaling pathway in rat brain after cortical contusion. Ann Clin Lab Sci, 2008, 38(1): 65-74

[10] KarinM, CaoY, GretenFR, et al.. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer, 2002, 2(4): 301-310

[11] HaydenMS, GhoshS. Shared principles in NF-κB signaling. Cell, 2008, 132(3): 344-362

[12] MedzhitovR, JanewayCJ. Innate immunity. N Engl J Med, 2000, 343(5): 338-344

[13] KawaiT, AkiraS. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol, 2010, 11(5): 373-384

[14] FaasMM, SchuilingGA, BallerJF, et al.. A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol, 1994, 171(1): 158-164

[15] FaasMM, BroekemaM, MoesH, et al.. Altered monocyte function in experimental preeclampsia in the rat. Am J Obstet Gynecol, 2004, 191(4): 1192-1198

[16] XiaGQ, XuDF, WuM, et al.. Expression of Toll-like receptor 4 in neonatal cord blood mononuclear cells in patients with preeclampsia. J Huazhong Univ Sci Technol [Med Sci], 2010, 30(5): 615-619

[17] MillerL, HuntJS. Regulation of TNF-alpha production in activated mouse macrophages by progesterone. Immunol, 1998, 160(10): 5098-5104

[18] YuanY, ShimizuI, ShenM, et al.. Effects of estradiol and progesterone on the proinflammatory cytokine production by mononuclear cells from patients with chronic hepatitis C. World J Gastroenterol, 2008, 4(14): 2200-2207

[19] WangZ, ZuoG, ShiXY, et al.. Progesterone administration modulates cortical TLR4/NF-κB signaling pathway after subarachnoid hemorrhage in male rats. Mediators Inflamm, 2011, 2011: 848309

[20] JonesLA, AnthonyJP, HenriquezFL, et al.. Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors. Immunology, 2008, 125(1): 59-69