Decrease in glomerulonephritis and Th1‐associated autoantibody production after progesterone treatment in NZB/NZW mice

Hughes, Grant C.; Martin, David; Zhang, Kang; Hudkins, Kelly L.; Alpers, Charles E.; Clark, Edward A.; Elkon, Keith B.

doi:10.1002/art.24548

Cited by 50 publications

(45 citation statements)

References 49 publications

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“…Based on the beneficial effects of progesterone in some human studies 20,21 and on the anti-inflammatory effects of progesterone, 23,36 we investigated if progesterone supplementation could prevent cervical remodeling and preterm birth in mice treated with LPS. Our studies demonstrated that progesterone pretreatment abrogated the cervical changes that lead to PTD in LPStreated mice.…”

Section: Discussionmentioning

confidence: 99%

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Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

González

Franzke

Yang

et al. 2011

The American Journal of Pathology

158

177

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Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication. Premature birth/delivery (PTD) is one of the most significant causes of perinatal mortality and morbidity in developed countries. Preterm infants suffer morbidities including respiratory distress, intraventricular hemorrhage, and cerebral palsy, among other serious diseases.1 These outcomes can have a life-long impact and more than $25 billion is spent each year to take care of these infants. Investigations to define the causes of PTD remain a challenge in the obstetrical field. Preterm labor is a multistage biochemical and biophysical process, during which changes in the myometrium and the cervix occur.The uterine cervix is a complex organ that undergoes extensive changes through gestation and parturition. These changes are a common first step in preterm parturition.2 As a gatekeeper for pregnancy, the cervix is a structural barrier that keeps the fetus inside the uterus until the end of gestation. Collagens, elastin, proteoglycans, and hyaluronate are responsible for the full tensile strength of the cervix.2 Ripening of the cervix is an important biological and clinical event required for a normal parturition. The process is gradual during pregnancy, with a fast final remodeling of the cervix before parturition. Increased collagen degradation and synthesis, and high activity of collagenases have been observed in the human cervix during final ripening.

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Section: Discussionmentioning

confidence: 99%

“…Several studies support the concept that progesterone has anti-inflammatory properties. 36,40 Progesterone suppresses estrogen-induced C3 expression in the mouse oviducts and uterus. 41 Another report showed that progesterone suppresses the complementmediated attack to allogenic chick embryos.…”

Section: Discussionmentioning

confidence: 99%

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

González

Franzke

Yang

et al. 2011

The American Journal of Pathology

158

177

View full text Add to dashboard Cite

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“…Various DMPA regimens have been described in animal models in an attempt to achieve DMPA serum concentrations similar to either endogenous progesterone levels or DMPA levels observed in humans (35)(36)(37). One such study established an intramuscular DMPA regimen for mice which would achieve similar DMPA plasma concentrations observed in women who use this hormone as breast cancer therapy (37).…”

Section: Discussionmentioning

confidence: 99%

The Contraceptive Depot Medroxyprogesterone Acetate Impairs Mycobacterial Control and Inhibits Cytokine Secretion in Mice Infected with Mycobacterium tuberculosis

et al. 2013

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dThe contraceptive depot medroxyprogesterone acetate (DMPA), with progestin as the single active compound, possesses selective glucocorticoid activity and can alter the expression of glucocorticoid receptor-regulated genes. We therefore propose that pharmacological doses of DMPA used for endocrine therapy could have significant immune modulatory effects and impact on susceptibility to, as well as clinical manifestation and outcome of, infectious diseases. We investigated the effect of contraceptive doses of DMPA in two different murine Mycobacterium tuberculosis models. Multiplex bead array analysis revealed that DMPA altered serum cytokine levels of tumor necrosis factor alpha (TNF-␣), granulocyte colony-stimulating factor (G-CSF), and interleukin 10 (IL-10) in C57BL/6 mice and gamma interferon (IFN-␥) in BALB/c mice. DMPA also suppressed antigen-specific production of TNF-␣, G-CSF, IL-10, and IL-6 and induced the production of IP-10 in C57BL/6 mice. In BALB/c mice, DMPA altered the antigen-specific secretion of IFN-␥, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and monocyte chemotactic protein 1 (MCP-1). Furthermore, we show that C57BL/6 mice treated with doses of DMPA, which result in serum concentrations similar to those observed in contraceptive users, have a significantly higher bacterial load in their lungs. Our data show for the first time that DMPA impacts tuberculosis (TB) disease severity in a mouse model and that the effects of this contraceptive are not confined to infections of the genital tract. This could have major implications for the contraceptive policies not only in developing countries like South Africa but also worldwide.

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“…In the context of immune-mediated diseases, the immunosuppressive effects of progestins may be important in developing new approaches to the prevention or treatment of diseases such as systemic lupus erythematosus or the complications of pregnancy such as preeclampsia (18,33). As MPs have proinflammatory and prothrombotic activities, their reduction would be expected to benefit conditions where both inflammation and vascular abnormalities contribute to pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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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Decrease in glomerulonephritis and Th1‐associated autoantibody production after progesterone treatment in NZB/NZW mice

Cited by 50 publications

References 49 publications

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

The Contraceptive Depot Medroxyprogesterone Acetate Impairs Mycobacterial Control and Inhibits Cytokine Secretion in Mice Infected with Mycobacterium tuberculosis

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

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