Intra‐uterine Growth Restriction Downregulates the Hepatic Toll Like Receptor‐4 Expression and Function

Ozlem Equils,Manikkavasagar Thamotharan,Sapna Singh,Sherin U Devaskar,Daning Lu,Semra Karaburun

doi:10.1080/17402520400008905

Abstract

Maternal starvation is a significant cause of intrauterine growth restriction (IUGR) in the world and increases the risk of infection in the neonate. We examined the effect of maternal starvation on Toll like receptor (TLR)4 expression in hepatic, splenic and intestinal tissues obtained from the adult IUGR offspring of prenatal calorie restricted rats. The hepatic TLR4 protein concentration was undetectable in the IUGR rats that had restricted milk intake during the suckling period (SM/SP; n = 4, p < 0.05) as compared to the normal growth controls (CM/CP; n=4), and access to ad lib milk intake during the sucking period partially corrected the hepatic TLR4 expression (SM/CP; n = 4). IUGR had no effect on the splenic (n = 4) or intestinal (n = 4) TLR4 mRNA levels. In the liver, IUGR led to a 20% increase in baseline tumor necrosis factor (TNF)-α mRNA expression ( p < 0.03) and a 70% increase in interleukin-1β (IL-1β) mRNA expression ( p < 0.008) as compared to the control rats (CM/CP; n = 7). LPS-induced hepatic TNF-α release was significantly higher in SM/SP as compared to CM/CP. We propose that IUGR dysregulates TLR4 expression and function in the offspring, which may help explain the increased risk of Gram-negative sepsis and inflammatory diseases in this population.

Highlights

In addition to genetic factors, environmental influences such as maternal nutrition play an important role in influencing the developing human immune system (reviewed in Chandra (2002))
We examined the expression of TLR4 in liver, spleen and intestinal tissue obtained from adult intrauterine growth restriction (IUGR) offspring of intrauterine starved rats by semi-quantitative reverse transcriptase (RT)-PCR and Western blot analyses
We hypothesized that IUGR down-modulates the TLR4 expression and this may help explain the increased risk of Gramnegative infections

Summary

Introduction

In addition to genetic factors, environmental influences such as maternal nutrition play an important role in influencing the developing human immune system (reviewed in Chandra (2002)). Adverse factors that impair fetal growth such as maternal malnutrition, hinder immunological maturation as well (Moscatelli et al 1976, Chandra 1975a,b 1981, Ferguson 1978, Hasselbalch et al 1999). Both animal and human data suggest that those who are small for gestation show persistent immunological impairment for several months or even years (Chandra 1975c, Beach et al 1982), and that they are at increased risk of infections with Gram-negative bacteria during the neonatal period and childhood (Simchen et al 2000). Defects at the level of expression of TLR4 could contribute to poor recruitment of antigen presenting cells, and T and B cells at the site of inflammation, resulting in suboptimal adaptive immune responses leading to increased risk of infections with Gram-negative bacteria

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Conclusion