IL-37 and 38 signalling in gestational diabetes

doi:10.1016/j.jri.2017.09.011

Journal of Reproductive Immunology

Volume 124, November 2017, Pages 8-14

https://doi.org/10.1016/j.jri.2017.09.011 Get rights and content

Highlights

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Gestational diabetes mellitus (GDM) involves in inflammatory, but the precise underlying mechanism is unclear.
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IL-37 and 38 play important role in autoimmunity, but their role in the development of GDM is unclear.
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Using histopathology and immunohistochemistry, we found that there was significant lower IL-37 but higher IL-38 in the both planceta from GDM group than that of Non-GDM group, which was consistent with peripheral IL-37 and IL-38. Such data was also supported by histopathology.
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Our data suggest that IL-37 protect pregnant women from the development of GDM.
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IL-38 produced in the chorionic villi and umbilical cords may be a response to local inflammation during the development of GDM.
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These data may provide useful information for the intervention for GDM.

Abstract

Gestational diabetes mellitus (GDM) is still a clinical challenge around world. Inflammation contributes to the pathogenesis of GDM, the precise underlying mechanism remains to be explored. IL-37 and 38 play important role in autoimmunity, but their role in the development of GDM is unclear. Using histopathology and immunohistochemistry, the thickness of the umbilical artery, the area of capillaries within the placental chorionic villi, and the production of IL-37/38 were determined. Placental mRNA of IL-37/IL-38 from GDM and Non-GMD was measured using qRT-PCR. serum IL-37/IL38 levels were evaluated, using ELISA.

IL-37 was reduced 49%, 48% or 57% in chorionic villi of placentas (P < 0.05), umbilical artery (P < 0.05), or umbilical vein (P < 0.05) from GDM women, respectively, compared to that from non-GDM women. In contrast, IL-38 was increased 3.3, 2.6, or 2.6 fold in chorionic villi (P < 0.01), umbilical artery (P < 0.05), umbilical vein (P < 0.05) from GDM women, respectively, compared to that from non-GDM women. IL-37 in GDM placentas or serum was reduced ∼52% or 33%, compared to that from Non-GDM subjects, respectively; whereas IL-38 in the GDM placentas or serum was increased by 1.6 fold or 1.3 fold, compare to that from Non-GDM, respectively.

Our data suggest that IL-37 protect pregnant women from the development of GDM. IL-38 produced in the chorionic villi and umbilical cords may be a response to local inflammation during the development of GDM. Such a dysregulated micro-environment may contribute to the development of GDM via an immune-mediated mechanism. These data may provide useful information for the intervention for GDM.

Introduction

Gestational diabetes mellitus (GDM) is defined as the first recognition of hyperglycemia during the gestational period with normal pre-gravid glucose tolerance (WorldHealthOrganizationGuideline, 2014). Uncontrolled high blood glucose in the pregnant women would cause many adverse outcomes for both mother and foetus. The consequences of diabetes in a pregnant woman include high incidence of malignant hypertension and caesarean, and increase risk of type 2 diabetes and metabolic syndrome postpartum (Barahona et al., 2005, Damm, 2009). In addition, there will be increasing risk of diabetes and obesity during childhood and adulthood for infants delivered from GDM mothers (Damm, 2009, Dabelea, 2007). The incidence of GDM is increasing worldwide, ranging from 1 to 14%, particularly in Asian mothers (American Diabetes A, 2004). The prevalence of GDM in China is either 4.3% or 17.5% based on the criteria of The American Diabetes Association (ADA) in 2009 (Yang et al., 2009), or International Association of Diabetes and Pregnancy Study Group (IADPSG) in 2012, respectively (Zhu et al., 2013).

Insulin sensitivity decreases physiologically by ∼60% during pregnancy to ensure sufficient glucose supply to the foetus for development (Catalano, 2014). Gestational insulin resistance is mainly due to placenta-produced hormones, e.g. prolactin and human chorionic gonadotropin, which are antagonists to insulin, in addition to increased food intake and weight gain during pregnancy (Ramos-Roman, 2011). Subsequently, there is up to a 50% increase in the size of β cells in pancreatic islands to compensate for the high blood glucose level (Retnakaran et al., 2008). The close correlation between inflammation and diabetes mellitus is well established (Donath and Shoelson, 2011). Highly produced pro-inflammatory cytokines, e.g. IL‐1β, IL-6, C reactive protein and TNF, interfere with the insulin signal pathway, causing insulin resistance (Kolb and Mandrup-Poulsen, 2005).

IL-37, originally named as IL-1 family member 7 (IL-1F7), shares the structural pattern of the IL-1 family, particularly with IL-18 (Nold et al., 2010). IL-37 is a novel anti-inflammatory cytokine that is involved in the development of autoimmune diseases, such as rheumatoid arthritis, psoriasis, Grave’s disease and systemic lupus erythematous, perhaps via inhibiting the expression and function of pro-inflammatory cytokines (Ye et al., 2015, Teng et al., 2014, Ye et al., 2014a).

IL-38 is an anti-inflammatory mediator, which acts via binding to IL-36Ra to suppress inflammation (van de Veerdonk et al., 2012). There is more than 40% similarity between IL-38 and IL‐1Ra or IL-38 and IL‐36Ra (Bensen et al., 2001, Kumar et al., 2000). The anti-inflammatory effect of IL-38 on peripheral blood mononuclear cells in vitro has been investigated, showing IL-38 supresses Th1 cells, IL-17 and IL-22 production (van de Veerdonk et al., 2012). However, IL-38 is not a classic antagonist for IL-36R, and the inhibitory effect of IL‐38 is dosage dependent, suggesting IL-38 is a partial receptor antagonist.

Considering GDM is a special type of diabetes with inflammatory modification within the placental chorionic villi and possibly the umbilical cord (Ozcaka et al., 2016), it is hypothesised that the pathological changes within the chorionic villi and the umbilical cord are partially mediated via IL-37 and IL-38. The precise underlying mechanism relating to these two cytokines will be discussed.

Section snippets

Clinical data

The gestational age of delivery in the GDM group was 3.7 years older than that in the Non-GDM group (32.22 ± 0.93 vs 28.52 ± 0.85 years, P < 0.01). However there was no significant difference in the systolic and diastolic blood pressure between the GDM and the Non-GDM groups (Table 1). Homeostasis model assessment of insulin resistance (HOMA-IR) was significantly higher in the GDM group than the Non-GDM group (2.25 ± 0.34 vs1.24 ± 0.2, P < 0.01). Fasting, 1 h and 2 h blood glucose levels were significantly

Discussion

In our current study there was significantly reduced IL-37 in the arteries and veins in the umbilical cord, as well as in the chorionic villi from GDM, compared to that of Non-GDM pregnant women. Such findings suggest that IL-37 may provide protection during pregnancy for healthy umbilical cords and chorionic villi, as the micro-environment in GDM is highly pro-inflammatory. In addition, mRNA expression of IL-1β, IL-6, TNF (proinflammatory cytokines) were significantly increased in the GDM

Study population

The placentae and umbilical cords were collected from GDM (n = 33) and non-GDM (n = 23) pregnant women from The Department of Obstetrics and Gynaecology, Shanghai Fifth People’s Hospital, Fudan University between February − August 2016. The clinical and demographical characteristics are listed (Table 1), including the weight and the height before their pregnancy, and the BMI before pregnancy by the formula: BMI (kg/m²) = Weight (kg)/height^{^2} (m²), HOMA-IR was calculated by another formula: HOMA-IR =

Conflict of interest

On the behalf of all of the authors, I would like to declare that there is no conflict of interest (Shisan Bao).

Funding

All the authors declare that there is no competing financial interest.

Acknowledgments

We appreciate the support from Bosch Small Equipment grant. We also acknowledge the financial support from the Shanghai Natural Scientific Foundation (No. 15ZR1433200).

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IL-37 and 38 signalling in gestational diabetes

Highlights

Abstract

Introduction

Section snippets

Clinical data

Discussion

Study population

Conflict of interest

Funding

Acknowledgments

Int. J. Gynaecol. Obstet.

J. Biol. Chem.

Arch. Oral Biol.

Placenta

American diabetes A, gestational diabetes mellitus

Diabetes Care

IL-37 protects against obesity-induced inflammation and insulin resistance

Nat. Commun.

Period of gestational diabetes mellitus diagnosis and maternal and fetal morbidity

Acta Obstet. Gynecol. Scand.

Identification of a novel human cytokine gene in the interleukin gene cluster on chromosome 2q12-14

J. Interferon Cytokine Res.

Trying to understand gestational diabetes

Diabet. Med.

The predisposition to obesity and diabetes in offspring of diabetic mothers