The Th2 cytokines IL-4 and IL-10 are not crucial for the completion of allogeneic pregnancy in mice

Svensson, Lovisa; Arvola, Marie; Sällström, Mary-Ann; Holmdahl, Rikard; Mattsson, Ragnar

doi:10.1016/s0165-0378(01)00065-1

Cited by 115 publications

(66 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This further suggests that Treg may promote tolerance by activating alternative pathways. These results are not surprising taking into account that the combination of IL-4 and IL-10 knockout in mice resulted in normal pregnancies, suggesting that neither maternal nor fetal production of IL-4 or IL-10 is crucial for the completion of pregnancies [18]. As we already proposed [28], it is tempting to speculate that in the IL-10-/IL-4-knockout mice, the lack of IL-10 or IL-4 -which are definitively related to successful pregnancy outcome in human and mice [6,9,50, 51] -could be "covered" or "by-passed" by high levels of other immunosuppressive molecules, i.e.…”

Section: Discussionmentioning

confidence: 74%

“…Th1/Th2 cytokine balance with Th2 predominance has been seen as a very important mechanism determining the survival of the fetus in the maternal uterus [6][7][8][9][10][11][12][13][14][15][16][17]. However, mice genetically deficient for IL-4 and IL-10 do not show disturbed pregnancy [18], suggesting that Th2 cells are not essential for normal pregnancy and alloreactive Th1 cells must be differently regulated, as already proposed [19][20][21].…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

et al. 2005

View full text Add to dashboard Cite

The mechanisms underlying immune tolerance during pregnancy are poorly understood. In this regard, Treg seem to play an important role in mediating maternal tolerance to the fetus. We proposed a crucial role of T regulatory cells (Treg) in avoiding immunological rejection of the fetus after observing diminished number and function of Treg in abortion-prone mice. We further confirmed the protective role of Treg during pregnancy by transferring pregnancy-induced Treg into abortion-prone mice, which prevented rejection. Here, we analyzed the mechanisms involved in Treg-mediated protection. As expected, Treg therapy prevented abortion, while expanding the peripheral and thymic Treg population. Surprisingly, the decidual levels of the Th1 cytokines IFN-c and TNF-a were not diminished after therapy. Interestingly, the mRNA levels of leukemia inhibitory factor, TGF-b and heme oxygenase-1 at the fetal-maternal interface were dramatically up-regulated after Treg transfer, while the levels of indolamine 2,3-dioxygenase remained unchanged. Our data suggest that Treg treatment can not prevent T cell infiltration or high Th1 levels but is able to create a privileged tolerant microenvironment at the fetal-maternal interface, further shedding light onto the molecular mechanisms involved in pregnancy tolerance.

show abstract

Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 97%

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

et al. 2005

View full text Add to dashboard Cite

show abstract

“…In nongestational tissues, IL-4 acts as an anti-inflammatory Th2 cytokine, but at the interface between chorion and decidua, it appears to fulfill the opposite function by stimulating production of inflammatory mediators such as PGs (38). However, expression of IL-4 does not appear to be essential for normal pregnancy (39), and elevated placental expression of IL-4 does not appear to be a feature of disorders such as pre-eclampsia (40). Expression of the proinflammatory cytokine IL-15 has been described in mouse (41) and human (41,42) placentas.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D and the Regulation of Placental Inflammation

Liu

Kaplan

Lagishetty

et al. 2011

The Journal of Immunology

182

118

View full text Add to dashboard Cite

The vitamin D-activating enzyme 1α-hydroxylase (CYP27B1) and vitamin D receptor (VDR) support anti-inflammatory responses to vitamin D in many tissues. Given the high basal expression of CYP27B1 and VDR in trophoblastic cells from the placenta, we hypothesized that anti-inflammatory effects of vitamin D may be particularly important in this organ. Pregnant wild type (WT) mice i.p. injected with LPS showed elevated expression of mouse Cyp27b1 (4-fold) and VDR (6-fold). Similar results were also obtained after ex vivo treatment of WT placentas with LPS. To assess the functional impact of this, we carried out ex vivo studies using placentas −/− for fetal (trophoblastic) Cyp27b1 or VDR. Vehicle-treated −/− placentas showed increased expression of IFN-γ and decreased expression of IL-10 relative to +/+ placentas. LPS-treated −/− placentas showed increased expression of TLR2, IFN-γ, and IL-6. Array analyses identified other inflammatory factors that are dysregulated in Cyp27b1−/− versus Cyp27b1+/+ placentas after LPS challenge. Data highlighted enhanced expression of IL-4, IL-15, and IL-18, as well as several chemokines and their receptors, in Cyp27b1−/− placentas. Similar results for IL-6 expression were observed with placentas −/− for trophoblastic VDR. Finally, ex vivo treatment of WT placentas with the substrate for Cyp27b1, 25-hydroxyvitamin D3, suppressed LPS-induced expression of IL-6 and the chemokine Ccl11. These data indicate that fetal (trophoblastic) vitamin D plays a pivotal role in controlling placental inflammation. In humans, this may be a key factor in placental responses to infection and associated adverse outcomes of pregnancy.

show abstract

“…Rather surprisingly, studies in IL-10 null mutant (IL-10 Ϫ/Ϫ ) mice indicate that this cytokine is not essential for normal pregnancy outcome, even in allogeneic pregnancies sired by MHC disparate males (31)(32)(33). Indeed, pregnancies in IL-10 Ϫ/Ϫ mice were characterized by consistently larger litter sizes and increased fetal weights (33).…”

mentioning

confidence: 99%

“…Indeed, pregnancies in IL-10 Ϫ/Ϫ mice were characterized by consistently larger litter sizes and increased fetal weights (33). However, reproductive experiments in IL-10 null mice have generally been conducted in pathogen-free barrier facilities where the artificially clean environment and use of antibiotics protect mice from environmental endotoxin (31)(32)(33). Mice with a null mutation in the IL-10 gene have substantially reduced tolerance to bacterial cell wall LPS with the lethal dose of LPS for IL-10 null mutant mice being 20-fold lower than that for wild-type mice, due to uncontrolled production of TNF-␣ and IFN-␥ in the absence of IL-10 (34).…”

mentioning

confidence: 99%

Essential Role for IL-10 in Resistance to Lipopolysaccharide-Induced Preterm Labor in Mice

Robertson

Skinner

Care

2006

The Journal of Immunology

174

139

View full text Add to dashboard Cite

IL-10 is highly expressed in the uterus and placenta and is implicated in controlling inflammation-induced pathologies of pregnancy. To investigate the role of IL-10 in regulating preterm labor, the response of IL-10 null mutant mice to low-dose LPS in late gestation was evaluated. When IL-10 null mutant C57BL/6 (IL-10−/−) and control (IL-10+/+) mice were administered LPS on day 17 of pregnancy, the dose of LPS required to elicit 50% preterm fetal loss was 10-fold lower in IL-10−/− mice than in IL-10+/+ mice. Surviving fetuses in IL-10−/− mice exhibited fetal growth restriction at lower doses of LPS than IL-10+/+ mice. Marked elevation of LPS-induced immunoactive TNF-α and IL-6 was evident in the serum, uterus, and placenta of IL-10−/− mice, and TNF-α and IL-6 mRNA expression was elevated in the uterus and placenta, but not the fetus. Serum IL-1α, IFN-γ, and IL-12p40 were increased and soluble TNFRII was diminished in the absence of IL-10, with these changes also reflected in the gestational tissues. Administration of rIL-10 to IL-10−/− mice attenuated proinflammatory cytokine synthesis and alleviated their increased susceptibility to preterm loss. Exogenous IL-10 also protected IL-10+/+ mice from fetal loss. These data show that IL-10 modulates resistance to inflammatory stimuli by down-regulating proinflammatory cytokines in the uterus and placenta. Abundance of endogenous IL-10 in gestational tissues is therefore identified as a critical determinant of resistance to preterm labor, and IL-10 may provide a useful therapeutic agent in this common condition.

show abstract

The Th2 cytokines IL-4 and IL-10 are not crucial for the completion of allogeneic pregnancy in mice

Cited by 115 publications

References 7 publications

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

Vitamin D and the Regulation of Placental Inflammation

Essential Role for IL-10 in Resistance to Lipopolysaccharide-Induced Preterm Labor in Mice

Contact Info

Product

Resources

About