Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-κB activation and enhancing SOCS1 expression

Su, Li; Sun, Yixi; Ma, Feng; Lü, Pingping; Huang, He‐Feng; Zhou, Jun

doi:10.1016/j.imlet.2009.07.003

Cited by 105 publications

(89 citation statements)

References 28 publications

(34 reference statements)

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“…2, progesterone inhibited particle production by RAW 264.7 cells stimulated by poly(I:C) in a dosedependent way, whereas estradiol over a similar range of concentrations failed to inhibit particle release by the stimulated cells. These findings are consistent with those of prior studies indicating differences in the effects of hormones on macrophages (25,38). As expected, dexamethasone potently inhibited particle release.…”

Section: Vol 18 2011 Sex Hormone Effects On Microparticle Release 1421supporting

confidence: 93%

“…As shown by studies of others, macrophages, including RAW 264.7 cells, do not have progesterone receptors. Nevertheless, these cells are able to respond to the effects of progesterone, although the effects of progesterone on NO production by macrophages have differed among studies (14,25,34,38). Along with data presented herein, these studies suggest that progesterone mediates its actions on macrophages by a mechanism other than a classical hormone receptor; the nature of this mechanism has not yet been identified, although it may reflect a role of a membrane receptor (10,11).…”

Section: Discussionmentioning

confidence: 54%

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Effects of Progesterone and Estradiol Sex Hormones on the Release of Microparticles by RAW 264.7 Macrophages Stimulated by Poly(I:C)

Pisetsky

Spencer

2011

Clin. Vaccine Immunol.

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Microparticles (MPs) are small membrane-bound vesicles that display proinflammatory and prothrombotic properties. These particles can be released by macrophages stimulated by ligands of the Toll-like receptors (TLRs) in a process that depends on nitric oxide (NO) production. Since sex hormones can modulate macrophage responses, we investigated the effects of progesterone and estradiol on macrophage particle release in vitro, comparing the responses with those induced by the glucocorticoid dexamethasone. As a model system for particle release, RAW 264.7 cells were stimulated in vitro with poly(I:C), a ligand of TLR3. Microparticles were measured by flow cytometry, while NO was measured by the Griess reaction. As the results of these studies showed, progesterone but not estradiol can block particle release by RAW264.7 cells treated with poly(I:C); dexamethasone was also active. Furthermore, while progesterone and dexamethasone inhibited NO production under the same culture conditions, neither agent blocked the production of particles stimulated by the NO donors dipropylenetriamine NONOate {(z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino] diazen-1-ium-1,2-diolate} and (z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2-diolate. Studies using RU486 to assess the role of hormone receptors indicated that while this agent blocked the inhibition of particle and NO production by dexamethasone, it did not affect the inhibition by progesterone. Together, these results indicate that progesterone but not estradiol can inhibit particle release by stimulated macrophages and suggest a mechanism that may contribute to the immunomodulatory effects of this sex hormone.

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Section: Vol 18 2011 Sex Hormone Effects On Microparticle Release 1421supporting

confidence: 93%

Section: Discussionmentioning

confidence: 54%

Effects of Progesterone and Estradiol Sex Hormones on the Release of Microparticles by RAW 264.7 Macrophages Stimulated by Poly(I:C)

Pisetsky

Spencer

2011

Clin. Vaccine Immunol.

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“…One interesting hypothesis may be progesterone modulation of aquaporin 4 channels [45], which are known to be associated with edema formation after ICH [46]. Another possibility lies in progesterone's known modulation of the NFκB pathway through TLRs [42,47,48], as supported by the present findings. Understanding the ICH-specific mechanisms of progesterone's action would improve the likelihood of its successful translation as a therapeutic.…”

Section: Discussionsupporting

confidence: 74%

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Lei

Wang²,

Jeong³

et al. 2015

Neuroendocrinology

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In models of acute brain injury, progesterone improves recovery through several mechanisms including modulation of neuroinflammation. Secondary injury from neuroinflammation is a potential therapeutic target after intracerebral hemorrhage (ICH). For potential translation of progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal collagenase (0.05-0.075 U) or autologous whole blood (35 μl) injection. Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively. Hematoma volume, brain water content (cerebral edema), complementary immunohistochemistry, multiplex cytokine arrays, and inflammatory proteins were assessed at prespecified time points after injury. Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory cytokines and Toll-like receptor-associated proteins were also decreased after progesterone (4 mg/kg) treatment (p < 0.01). Progesterone-treated young female mice showed no detectable effects. Exogenous progesterone improved short- and long-term neurobehavioral recovery and modulated neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.

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“…Progesterone can act at both progesterone and glucocorticoid receptors [41] . There is some evidence that progesterone inhibits TLR4 responses in macrophages by suppressing activation of NF-B and enhancing suppressor of cytokine signalling (SOCS1) [42] . However, the exact mechanisms of how sex hormones alter innate immune signalling have yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Menstrual Cycle Influences Toll-Like Receptor Responses

Dennison¹,

McKernan²,

Scully³

et al. 2012

Neuroimmunomodulation

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Background: Toll-like receptors (TLRs) are pattern recognition receptors that play an important role as mediators of innate immunity. Human studies have shown changes in endometrial TLR expression during the menstrual cycle and during pregnancy. Our objective was to measure peripheral TLR activity over the course of the menstrual cycle. Methods: We recruited 11 healthy females, and using ELISA we measured sex hormone levels and IL-1β, IL-6, IL-8 and TNF-α following stimulation of whole blood with different TLR agonists during follicular, and early and late luteal phases of the menstrual cycle. Results: During the follicular phase, we observed lower levels of IL-6 and TNF-α following stimulation with the TLR2 agonist HKLM when compared with the early luteal phase; lower levels of IL-1β, IL-6 and TNF-α following stimulation with the TLR4 agonist LPS, and lower levels of IL-1β and TNF-α following stimulation with the TLR5 agonist flagellin. Decreased IL-6 levels in the late compared to the early luteal phase were also observed following stimulation with the TLR5 agonist flagellin. Compared with the follicular phase, the late luteal phase of the cycle resulted in decreased levels of IL-1β and TNF-α following stimulation with the TLR1/TLR2 agonist Pam3CSK and the TLR6/TLR2 agonist FSL1, as well as decreased levels of TNF-α following stimulation with the TLR8 agonist ssRNA40. There were no differences in cytokine release across the menstrual cycle following stimulation with the TLR3 agonist polyriboinosinic polyribocytidylic acid, or the TLR7 agonist Imiquimod. Conclusion: This study is the first to demonstrate that TLR responsivity in peripheral blood fluctuates throughout the menstrual cycle.

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Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-κB activation and enhancing SOCS1 expression

Cited by 105 publications

References 28 publications

Effects of Progesterone and Estradiol Sex Hormones on the Release of Microparticles by RAW 264.7 Macrophages Stimulated by Poly(I:C)

Effects of Progesterone and Estradiol Sex Hormones on the Release of Microparticles by RAW 264.7 Macrophages Stimulated by Poly(I:C)

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Menstrual Cycle Influences Toll-Like Receptor Responses

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