Calcifediol Decreases Interleukin-6 Secretion by Cultured Human Trophoblasts From GDM Pregnancies

Abstract

Gestational diabetes mellitus (GDM) is often characterized by low maternal calcifediol (25OHD) and high inflammation levels. This study aimed to determine whether placental protein expressions of CYP27B1, vitamin D receptor (VDR), and CYP24A1 are impaired in GDM and to investigate the effect of a 25OHD treatment on IL-6 secretion by GDM trophoblasts compared with normoglycemic (NG) trophoblasts. Placental tissue samples were harvested to determine protein expression of CYP27B1, VDR, and CYP24A1 by immunoblots. Isolated trophoblasts were stimulated with 25OHD concentrations (25 to 2000 nM) once a day for 3 days and IL-6 secretion was quantified (ELISA). We recruited 17 NG women, 19 women with GDM treated with diet and exercise alone (GDM-d) and 9 women with GDM who necessitated insulin therapy (GDM-i). Protein expressions of CYP27B1 and VDR were significantly higher in placental tissue from GDM-d women compared with NG women (both P = 0.02), whereas no differences were detected between GDM-i and NG placental tissues. In cultured trophoblasts (two groups; n = 5 NG and n = 5 GDM-d), exposure to increasing 25OHD concentrations significantly decreased IL-6 secretion in the GDM-d group only (P = 0.006). After treatment with 25OHD (2000 nM), IL-6 secretion was lower in the GDM-d group compared with the NG group (P = 0.03). Our results suggest an upregulation of the VDR-1,25(OH)2D complex bioavailability in GDM-d placentas, possibly reflecting a compensatory mechanism aiming to ensure that vitamin D can exert its genomic and nongenomic effects in the target cells of the placental-fetal unit. Our findings support an anti-inflammatory effect of vitamin D at the feto-maternal interface in GDM-d pregnancies.

Immunoendocrine Dysregulation during Gestational Diabetes Mellitus: The Central Role of the Placenta

“…Indeed, VD-response elements are present in the human insulin receptor gene, which is activated by VDR-calcitriol [ 210 , 211 ]. Accordingly, recent reports support that calcitriol protects against insulin resistance and exacerbated inflammation at the MPFU in GDM [ 138 , 212 ]. Therefore, VD deficiency is associated with blood glucose and insulin alterations, partially explaining the suggested implication of VD deficiency as an independent risk factor for GDM [ 203 ].…”

“…The placenta presents not only an active endocrine function, but also an important immune-modulatory action characterized by the synthesis of diverse cytokines, chemokines, and adipokines, as well as their receptors. The implication of pro-inflammatory cytokines in GDM pathology has been demonstrated in numerous studies [ 135 , 136 , 137 , 138 ]. Gene microarray experiments in GDM placentae showed increased expression of genes for stress-activated and inflammatory responses, with upregulation of interleukins, leptin, and TNF-α receptors and their downstream molecular adaptors [ 139 ].…”

IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies

“…The placental common repertoire of cytokines also becomes overexpressed in a diabetic environment [ 274 , 275 , 276 ]. Data from the literature show an increased IL-6 mRNA expression in GDM placentas [ 115 , 163 , 164 , 165 , 166 ], possibly associated with the enhanced macrophage infiltration in GDM placentas, compared to a physiological pregnancy [ 163 , 168 ]. However, no significant differences in the IL-6 mRNA expression in placentas of women with GDM, compared with healthy controls were also reported [ 168 , 169 ].…”

Vitamin D and the Immune System. When? Why? How?

“…The immune system's response to infections is a very complex process in which multiple cell types and multiple soluble factors, such as cytokines, chemokines and hormones participate [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Vitamin D is involved both in the innate and in the adaptive immune responses to viral and bacterial infections [14].…”