Estrous Cycle and Gestational Age-Dependent Expression of Members of the Interleukin-36 Subfamily in a Semi-Allogeneic Model of Infected and Non-Infected Murine Pregnancy

Murrieta-Coxca, José Martín; Gómez‐Chávez, Fernando; Baeza-Martínez, Damariz Adriana; Cancino-Díaz, Mario E.; Cancino‐Díaz, Juan C.; Pérez‐Tapia, Sonia Mayra; Reyes‐Maldonado, Elba; Rodríguez‐Martínez, Sandra

doi:10.3389/fimmu.2016.00376

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…We extend these findings here in the context of a highly relevant STI pathogen, HSV-2. Consistent with a recent clinical report, we found that HSV-2 robustly induces IL-36γ [29]. Furthermore, we found that pretreatment with IL-36γ significantly decreased vaginal viral replication in vitro .…”

Section: Discussionsupporting

confidence: 92%

“…In the upper female reproductive tract it has been shown that Listeria monocytogenes infection robustly induced the IL-36 cytokines in the uteri of pregnant mice, however, the impact of the IL-36 cytokines on infection and pregnancy is still unclear [29]. Recently, our laboratory measured increased levels of IL-36γ in cervicovaginal lavages (CVLs) from cervical cancer patients [30].…”

Section: Introductionmentioning

confidence: 99%

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IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

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Herpes simplex virus 2 (HSV-2) causes a persistent, lifelong infection that increases risk for sexually transmitted infection acquisition. Both the lack of a vaccine and the need for chronic suppressive therapies to control infection presents the need to further understand immune mechanisms in response to acute HSV-2 infection. The IL-36 cytokines are recently identified members of the IL-1 family and function as inflammatory mediators at epithelial sites. Here, we first used a well-characterized three-dimensional (3-D) human vaginal epithelial cell (VEC) model to understand the role of IL-36γ in the context of HSV-2 infection. In 3-D VEC, IL-36γ is induced by HSV-2 infection, and pretreatment with exogenous IL-36γ significantly reduced HSV-2 replication. To assess the impact of IL-36γ treatment on HSV-2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL-36γ treatment in mice prior to lethal intravaginal challenge significantly limited vaginal viral replication, delayed disease onset, decreased disease severity, and significantly increased survival. We demonstrated that IL-36γ treatment transiently induced pro-inflammatory cytokines, chemokines, and antimicrobial peptides in murine lower female reproductive tract (FRT) tissue and vaginal lavages. Induction of the chemokines CCL20 and KC in IL-36γ treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36γ drives the transient production of immune mediators and promotes PMN recruitment in the vaginal microenvironment that increases resistance to HSV-2 infection and disease. Our data indicate that IL-36γ may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

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“…The presence of bacterial and viral infections impairs trophoblast invasion and disrupts endothelial tubulogenesis ([ 14 , 15 ] and reviewed in [ 16 ]). Furthermore, our previous report showed enhanced expression of IL-36 members in murine uterine tissue infected by Listeria monocytogenes [ 11 , 12 , 17 ]. To assess the association of microbial components and IL-36 cytokines in trophoblast cells, the effect of LPS and poly I:C stimulation was investigated.…”

Section: Resultsmentioning

confidence: 99%

“…The role of the IL-36 family in pregnancy remains largely unknown. In mice, high expression of IL-36 was reported in the uterus at estrus stage and during labor, and is highly induced by Listeria monocytogenes, demonstrating its role in inflammation and maternal immune response to pathogens [ 11 , 12 ]. In humans, a recent report demonstrated enhanced levels of IL-36Ra in plasma samples of pregnant compared to non-pregnant women, and decreased IL-36Ra levels in extracellular vesicles from preeclampsia versus healthy placentas [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Role of IL-36 Cytokines in the Regulation of Angiogenesis Potential of Trophoblast Cells

Murrieta-Coxca

Gutiérrez-Samudio

El-Shorafa

et al. 2020

IJMS

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IL-36 cytokines (the agonists IL-36α, IL-36β, IL-36γ, and the antagonist IL-36Ra) are expressed in the mouse uterus and associated with maternal immune response during pregnancy. Here, we characterize the expression of IL-36 members in human primary trophoblast cells (PTC) and trophoblastic cell lines (HTR-8/SVneo and JEG-3) and upon treatment with bacterial and viral components. Effects of recombinant IL-36 on the migration capacity of trophoblastic cells, their ability to interact with endothelial cells and the induction of angiogenic factors and miRNAs (angiomiRNAs) were examined. Constitutive protein expression of IL-36 (α, β, and γ) and their receptor (IL-36R) was found in all cell types. In PTC, transcripts for all IL-36 subtypes were found, whereas in trophoblastic cell lines only for IL36G and IL36RN. A synthetic analog of double-stranded RNA (poly I:C) and lipopolysaccharide (LPS) induced the expression of IL-36 members in a cell-specific and time-dependent manner. In HTR-8/SVneo cells, IL-36 cytokines increased cell migration and their capacity to interact with endothelial cells. VEGFA and PGF mRNA and protein, as well as the angiomiRNAs miR-146a-3p and miR-141-5p were upregulated as IL-36 response in PTC and HTR-8/SVneo cells. In conclusion, IL-36 cytokines are modulated by microbial components and regulate trophoblast migration and interaction with endothelial cells. Therefore, a fundamental role of these cytokines in the placentation process and in response to infections may be expected.

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“…Deregulated expression of IL-36 cytokines could be associated with the development of pregnancy complications. Using a mouse model of pregnancy infected by Listeria monocytogenes, we described a differential and strong mRNA and protein expression of IL-36 (α, β, γ) as well as IL-36Ra and IL-36R in the uterus [141]. We also observed that high levels of IL-36 cytokines in infected animals enhances inflammatory activity, associated with a high ratio of fetal resorption [142].…”

Section: Il-36 Cytokines In Female Reproductive Tissues and Pregnancymentioning

confidence: 99%

IL-36 Cytokines: Regulators of Inflammatory Responses and Their Emerging Role in Immunology of Reproduction

Murrieta-Coxca

Rodríguez‐Martínez

Cancino-Díaz

et al. 2019

IJMS

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The IL-36 subfamily of cytokines has been recently described as part of the IL-1 superfamily. It comprises three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ), their receptor (IL-36R), and one antagonist (IL-36Ra). Although expressed in a variety of cells, the biological relevance of IL-36 cytokines is most evident in the communication between epithelial cells, dendritic cells, and neutrophils, which constitute the common triad responsible for the initiation, maintenance, and expansion of inflammation. The immunological role of IL-36 cytokines was initially described in studies of psoriasis, but novel evidence demonstrates their involvement in further immune and inflammatory processes in physiological and pathological situations. Preliminary studies have reported a dynamic expression of IL-36 cytokines in the female reproductive tract throughout the menstrual cycle, as well as their association with the production of immune mediators and cellular recruitment in the vaginal microenvironment contributing to host defense. In pregnancy, alteration of the placental IL-36 axis has been reported upon infection and pre-eclampsia suggesting its pivotal role in the regulation of maternal immune responses. In this review, we summarize current knowledge regarding the regulatory mechanisms and biological actions of IL-36 cytokines, their participation in different inflammatory conditions, and the emerging data on their potential role in normal and complicated pregnancies.

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Estrous Cycle and Gestational Age-Dependent Expression of Members of the Interleukin-36 Subfamily in a Semi-Allogeneic Model of Infected and Non-Infected Murine Pregnancy

Cited by 8 publications

References 27 publications

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Role of IL-36 Cytokines in the Regulation of Angiogenesis Potential of Trophoblast Cells

IL-36 Cytokines: Regulators of Inflammatory Responses and Their Emerging Role in Immunology of Reproduction

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