Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls

Abstract

Objectives: The IGF system is central to fetal growth. Recently, the relationships between cytokines and the IGF system have been shown in specific tissues. It is unknown whether these occur in the placenta. The aim of this study was to assess whether interleukin-6 (IL-6) modulated the IGF system. Methods: Whole villous tissue and cord serum were collected from fetal growth restriction (FGR) neonates diagnosed before birth with altered Doppler velocimetry and controls. Sixteen FGR and 20 controls, born after week 32 of gestation from elective Caesarean sections, were compared. Total RNA was extracted from the placenta samples, reverse transcribed, and real-time quantitative reverse transcriptase (RT)-PCR was performed to quantify cDNA for IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-2, and IL-6. The same proteins were assayed in placenta lysates and cord serum using specific commercial kits and western immunoblotting. Results: FGR subjects had significantly more IGFBPs-1 and -2, and IL-6 mRNA and corresponding proteins in the placenta. In particular, the less phosphorylated isoforms of IGFBP-1 were highly increased. IL-6 and IGFBPs-2 mRNA, and IL-6 and IGFBP-1 peptides were positively and significantly correlated in the placenta. The IGF-II peptide was also significantly increased in FGR placentas. In cord serum, IGFBPs-1 and -2 were significantly more elevated in the FGR neonates. Serum IL-6 was significantly and positively correlated with both IGFBP-1 and IGFBP-2. Conclusions: The placenta of FGR neonates has higher IGF-II, IGFBP-1, IGFBP-2, and IL-6 contents compared with controls. At birth, IGFBPs-1 and -2 are increased in the cord blood of FGR neonates. IL-6 and IGFBP-2 gene expressions are closely related in the placenta. We suggest that the increase in IL-6 and IGFBP-2 could be subsequent to hypoxia and nutrient deficiency. As IGFBP-2 has a strong affinity for IGF-II, which is crucial for fetal growth, it could be an important bioregulator of IGF-II in the placenta.European Journal of Endocrinology 155 567-574

The IGF Axis in Baboon Pregnancy: Placental and Systemic Responses to Feeding 70% Global Ad Libitum Diet

“…Maternal IGF-I in its bound form does not cross the placental barrier in rats; however, the placenta transports free IGF [36]. IGF-I gene expression is high in the human placenta at term, but the corresponding protein is undetectable [37,38]. In agreement with data published by Carter and Han, IGF-I mRNA expression in our study was detected in syncytiotrophoblast [5].…”

The impact of ovarian stimulation for IVF on the developing embryo

“…Elevated expression levels of paternally imprinted gene IGF2 in the placenta have been correlated with foetal growth restriction in humans (Street et al 2006) and sheep (de Vrijer et al 2006) and with early embryonic lethality of somatic cell nuclear transferderived cows (Oishi et al 2006). Since low birthweight in humans may be an important risk factor for the development of neurological disorders and adult-onset diseases such as coronary heart disease, stroke, hypertension, type II diabetes and osteoporosis, ovarian stimulation could even have adverse effects in adult life (Fleming et al 2004).…”

Genomic imprinting as an adaptative model of developmental plasticity

“…The discrepancies may partly be due to a failure to take into account the impact of changes in the levels of the circulating non-imprinted binding proteins which alter IGF2 bioavailability, IGFBPs. Serum level of several IGFBPs has been found to correlate with birth weight and may be modulated by in utero nutrition [57,58,61,65]. This relationship with proteins which modulate bioavailability makes Igf2 a particularly challenging model for assessing phenotypic plasticity and imprinted gene dosage and also suggests that the effective dosage of imprinted genes may be modulated post transcriptionally by non-imprinted pathways.…”