Differential Modulation of TLR3- and TLR4-Mediated Dendritic Cell Maturation and Function by Progesterone

Jones, Leigh Ann; Kreem, Shrook Abdulla; Shweash, Muhannad; Paul, Andrew; Alexander, James; Roberts, Craig W.

doi:10.4049/jimmunol.0901155

Cited by 86 publications

(72 citation statements)

References 56 publications

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“…In mice, increased morbidity during toxoplasmosis has been associated with estradiol levels, while gonadectomy reduces pathogenesis of toxoplasmosis [3]. A high concentration of progesterone has also been shown to increase susceptibility to T. gondii infection during pregnancy by suppressing production of IL-12 and IFN-γ [47] and, therefore, suppressing a type-1 response utilizing the progesterone and glucocorticoid receptors [48]. In the present work, increased production of hormones by T. gondii -infected villous explants may be a result of an evasion strategy orchestrated by the parasite.…”

Section: Discussionmentioning

confidence: 99%

Azithromycin is able to control Toxoplasma gondii infection in human villous explants

et al. 2014

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BackgroundAlthough Toxoplasma gondii infection is normally asymptomatic, severe cases of toxoplasmosis may occur in immunosuppressed patients or congenitally infected newborns. When a fetal infection is established, the recommended treatment is a combination of pyrimethamine, sulfadiazine and folinic acid (PSA). The aim of the present study was to evaluate the efficacy of azithromycin to control T. gondii infection in human villous explants.MethodsCultures of third trimester human villous explants were infected with T. gondii and simultaneously treated with either PSA or azithromycin. Proliferation of T. gondii, as well as production of cytokines and hormones by chorionic villous explants, was analyzed.ResultsTreatment with either azithromycin or PSA was able to control T. gondii infection in villous explants. After azithromycin or PSA treatment, TNF-α, IL-17A or TGF-β1 levels secreted by infected villous explants did not present significant differences. However, PSA-treated villous explants had decreased levels of IL-10 and increased IL-12 levels, while treatment with azithromycin increased production of IL-6. Additionally, T. gondii-infected villous explants increased secretion of estradiol, progesterone and HCG + β, while treatments with azithromycin or PSA reduced secretion of these hormones concurrently with decrease of parasite load.ConclusionsIn conclusion, these results suggest that azithromycin may be defined as an effective alternative drug to control T. gondii infection at the fetal-maternal interface.

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Section: Discussionmentioning

confidence: 99%

Azithromycin is able to control Toxoplasma gondii infection in human villous explants

et al. 2014

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“…P4 can bind to glucocorticoid receptors, which are more abundant in the immune system than are PR, and may represent an alternative mechanism for P4-induced changes in immune function (57). P4 inhibits TLR-induced cytokine production as well as surface receptor expression via PR and glucocorticoid receptors in DC (57). Progesterone suppresses innate immune responses, including macrophage and NK cell activity as well as NF-B signal transduction (58,59).…”

Section: Sex Steroidsmentioning

confidence: 97%

“…secretion of TNF-␣) of DC from female rats (56). P4 can bind to glucocorticoid receptors, which are more abundant in the immune system than are PR, and may represent an alternative mechanism for P4-induced changes in immune function (57). P4 inhibits TLR-induced cytokine production as well as surface receptor expression via PR and glucocorticoid receptors in DC (57).…”

Section: Sex Steroidsmentioning

confidence: 99%

Immune Cells Have Sex and So Should Journal Articles

2012

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Males and females have the same immunological cells, proteins, and pathways in place to protect against the development of disease. The kinetics, magnitude, and skewing of the responses mounted against pathogens, allergens, toxins, or self-antigens, however, can differ dramatically between the sexes. Generally, females mount higher innate and adaptive immune responses than males, which can result in faster clearance of pathogens but also contributes to increased susceptibility to inflammatory and autoimmune diseases in females compared with males. Hormonal and genetic factors contribute significantly to sex differences in immune function and disease pathogenesis. In particular, the expression of X-linked genes and microRNA as well as sex steroid hormones signaling through hormone receptors in immune cells can affect responses to immunological stimuli differently in males and females. Despite data illustrating profound differences between the sexes in immune function, sex differences in the pathogenesis of disease are often overlooked in biomedical research. Establishing journal policies that require authors to report the sex of their cells, animals, and subjects will improve our understanding of the pathogenesis of diseases, with the long-term goal of personalizing treatments for immune-mediated diseases differently for males and females in an effort to protect us equally.

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“…In reproductive tissues, PR is known to interact with STAT3 (46), an important inducer of development and survival in T REG cells. It may also be that PR influences CD4 + T cell development through effects in the thymus (47), or that PR influences the differentiation of naïve CD4 + T cells via effects in mDCs or macrophages (48), as suggested by selective sex-specific effects of PR loss on macrophage activation (Fig. 8A).…”

Section: Discussionmentioning

confidence: 99%

Altered IgG autoantibody levels and CD4⁺T cell subsets in lupus-proneNba2mice lacking the nuclear progesterone receptor

2015

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Important interactions between female reproduction and autoimmunity are suggested by the female-predominance of systemic lupus erythematosus (SLE) and other autoimmune diseases and the amelioration of certain autoimmune diseases during pregnancy. Sexually dimorphic risk of developing SLE involves modulation of genetic risk by environmental factors, sex hormones and non-hormonal factors encoded on the sex chromosomes. In some lupus models, estrogen, via estrogen receptor alpha (ER-α), enhances production of highly pathogenic IgG2a/c autoantibodies (autoAbs). Some studies indicate that treatment with progesterone, a chief female reproductive steroid, can suppress IgG2a/2c autoAb production. Little is known about how endogenous progesterone impacts lupus autoimmunity. To investigate this, we introduced a disruptive progesterone receptor (PR) gene mutation into lupus-prone mice and tracked the development of spontaneous IgG autoAbs. Here, we present evidence that PR can suppress the emergence of class-switched IgG2c autoAbs, suggesting that PR and ER-α counter-regulate a critical step in lupus autoimmunity. PR's control of IgG2c autoAb production correlates with alterations in the relative abundance of splenic T follicular helper (TFH) cells and non-TFH CD4+ T cells, especially regulatory T cells (TREGS). Surprisingly, PR also appears to help maintain sexually dimorphic abundance of splenic leukocytes, a feature common to many mouse models of SLE. Together our results identify a novel molecular link between female reproduction and lupus autoimmunity. Further investigation into the immunomodulatory functions of PR promises to inform reproductive health care in women and offer mechanistic insight into important immunologic phenomena of pregnancy.

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Differential Modulation of TLR3- and TLR4-Mediated Dendritic Cell Maturation and Function by Progesterone

Cited by 86 publications

References 56 publications

Azithromycin is able to control Toxoplasma gondii infection in human villous explants

Azithromycin is able to control Toxoplasma gondii infection in human villous explants

Immune Cells Have Sex and So Should Journal Articles

Altered IgG autoantibody levels and CD4⁺T cell subsets in lupus-proneNba2mice lacking the nuclear progesterone receptor

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Differential Modulation of TLR3- and TLR4-Mediated Dendritic Cell Maturation and Function by Progesterone

Cited by 86 publications

References 56 publications

Azithromycin is able to control Toxoplasma gondii infection in human villous explants

Azithromycin is able to control Toxoplasma gondii infection in human villous explants

Immune Cells Have Sex and So Should Journal Articles

Altered IgG autoantibody levels and CD4+T cell subsets in lupus-proneNba2mice lacking the nuclear progesterone receptor

Contact Info

Product

Resources

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Altered IgG autoantibody levels and CD4⁺T cell subsets in lupus-proneNba2mice lacking the nuclear progesterone receptor