Cnr2 Deficiency Confers Resistance to Inflammation-Induced Preterm Birth in Mice

Sun, Xiaofei; Cappelletti, Monica; Li, Yingju; Karp, Christopher L.; Divanovic, Senad; Dey, Sudhansu K.

doi:10.1210/en.2014-1387

Cited by 19 publications

(21 citation statements)

References 61 publications

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“…As well as cytokines, immune regulators that attenuate TLR-mediated inflammation can impact susceptibility to LPS-induced preterm birth. For example, the cannabinoid receptor Cnr2 modulates dendritic cell production of IL10 and IL6, such that mice genetically deficient in Cnr2 are resistant to LPS-induced preterm birth55. Prostaglandins synthesized after Ptgs2 induction by LPS administration contribute to cervical ripening and other endpoints of parturition, and suppression of Ptgs2 with specific inhibitors can modulate LPS-induced PTD rate56.…”

Section: Discussionmentioning

confidence: 99%

Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth

Chin

Dorian

Hutchinson

et al. 2016

Sci Rep

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Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (−)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth

Chin

Dorian

Hutchinson

et al. 2016

Sci Rep

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“…29,30 A recent study provided a supporting evidence for the role of IL-10 in preventing preterm birth as increased IL-10 production occurring via augmented cAMP accumulation contributes to resistance to LPS-induced preterm birth in mice with deficiency in G-protein coupled receptor CB2. 109 …”

Section: Il-10 Dysregulation In Adverse Pregnancy Outcomesmentioning

confidence: 99%

Interleukin-10: A Pleiotropic Regulator in Pregnancy

Cheng

Sharma

2014

Am J Reprod Immunol

138

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Pregnancy is a unique and well-choreographed physiological process that involves intricate interplay of inflammatory and anti-inflammatory milieu, hormonal changes, and cellular and molecular events at the maternal-fetal interface. IL-10 is a pregnancy compatible cytokine that plays a vital role in maintaining immune tolerance. A wide array of cell types including both immune and non-immune cells secret IL-10 in an autocrine and paracrine manner. IL-10 binds to a specific receptor complex and activates JAK-STAT and PI3K-Akt signaling pathways while inhibiting NF-κB signaling pathway. IL-10 exerts its anti-inflammatory effects mainly by decreasing pro-inflammatory cytokines such as IL-1, IL-6, IL-12, and TNF-α, by inducing heme oxygenase-1, and by inhibiting antigen presentation via blocking major histocompatibility complex (MHC) class II expression. Prior studies from our group and others have shown that IL-10 also functions as a potent protector against vascular dysfunction, and enhancement of IL-10 may serve as an immunotherapeutic intervention to treat adverse pregnancy outcomes. This review seeks to critically evaluate the archetypal functions of IL-10 as an immune suppressive factor as well as its novel functions as a vascular protector and modulator of endoplasmic reticulum (ER) stress and autophagy in the context of normal and adverse pregnancy outcomes.

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“…It is well known that CB2 receptors are expressed in immune, hematopoietic and in almost all peripheral blood immune cells (Pacher & Mechoulam 2011), and its expression can be influenced by various inflammatory agents, e.g., LPS (Carlisle et al 2002, Klein et al 2003. Sun et al (2014) observed that CB2-KO mice had higher serum levels of IL-10 and lower levels of pro-inflammatory cytokines in response to LPS challenge compared with WT controls.…”

Section: Discussionmentioning

confidence: 94%

“…Lazzarin et al (2004) have shown that changes in progesterone levels and FAAH expression are well correlated during the menstrual cycle. The CB2-KO mice are resistant to LPS-driven preterm birth and the endotoxin was unable to decrease maternal progesterone serum levels compared with WT mice (Sun et al 2014), suggesting that ovaries deficient in CB2 are protected from adverse effects of inflammatory insults. In addition, in a model of LPS-induced embryonic resorption, the changes in FAAH activity correlated with changes in progesterone serum levels (Wolfson et al 2013).…”

Section: Discussionmentioning

confidence: 97%

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Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Bariani¹,

Rubio²,

Cella³

et al. 2015

Reproduction

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Prematurity is the leading cause of perinatal morbidity and mortality worldwide. There is a strong causal relationship between infection and preterm births. Intrauterine infection elicits an immune response involving the release of inflammatory mediators like cytokines and prostaglandins (PG) that trigger uterine contractions and parturition events. Anandamide (AEA) is an endogenous ligand for the cannabinoid receptors CB1 and CB2. Similarly to PG, endocannabinoids are implicated in different aspects of reproduction, such as maintenance of pregnancy and parturition. Little is known about the involvement of endocannabinoids on the onset of labor in an infectious milieu. Here, using a mouse model of preterm labor induced by lipopolysaccharide (LPS), we explored changes on the expression of components of endocannabinoid system (ECS). We have also determined whether AEA and CB antagonists alter PG production that induces labor. We observed an increase in uterine N-acylphosphatidylethanolaminespecific phospholipase D expression (NAPE-PLD, the enzyme that synthesizes AEA) upon LPS treatment. Activity of catabolic enzyme fatty acid amide hydrolase (FAAH) did not change significantly. In addition, we also found that LPS modulated uterine cannabinoid receptors expression by downregulating Cb2 mRNA levels and upregulating CB1 protein expression. Furthermore, LPS and AEA induced PGF2a augmentation, and this was reversed by antagonizing CB1 receptor. Collectively, our results suggest that ECS may be involved in the mechanism by which infection causes preterm birth.

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Cnr2 Deficiency Confers Resistance to Inflammation-Induced Preterm Birth in Mice

Cited by 19 publications

References 61 publications

Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth

Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth

Interleukin-10: A Pleiotropic Regulator in Pregnancy

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

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