Toll-like receptor 4-mediated immune stress in pregnant rats activates STAT3 in the fetal brain: role of interleukin-6.
Prenatal exposure to pathogens induces long lasting effect on brain function and plasticity. It is unclear how maternal immune stress impacts fetal brain development. Immune challenged pregnant rats induce the production of inflammatory cytokines including tumor necrosis factor (TNF)α, interleukin (IL)1β, and IL-6. IL-6 crosses the placenta but its mechanism of action on fetal brain is unclear.



Gestation day 15 (GD15) rats were given a single injection of lipopolysaccharide (LPS) (100 µg/kg) in the presence or the absence of an IL-6 neutralizing antibody (IL-6Ab, 10 µg/kg). The activation of the intracellular signal of IL-6; signal transducer and activator of transcription (STAT3) and levels of glucocorticoids (GCs) were monitored in fetal brains.



LPS administration to GD15 rats significantly increased the phosphorylation levels of STAT3 in fetal brains. Such activation was blunted by IL-6Ab. LPS induced a significant rise in GCs in the plasma of dams but not in fetal brains. IL-6Ab significantly reduced LPS-induced GCs in maternal plasma.



Toll-like receptor 4 (TLR4)-induced activation of the maternal innate immune system affects fetal brains likely via the mobilization of IL-6/STAT3 pathway. In contrast, TLR4-stimulated maternal GCs release is less likely to play a significant role in fetal brain development.
Department of Physiology, Health Sciences Centre, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
Abdeslam
A
Mouihate
Department of Physiology, Health Sciences Centre, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
Heba
H
Mehdawi
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001921:Brain / Q000196:embryology*; D016923:Cell Death; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D007107:Immune System; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D009474:Neurons / Q000166:cytology; D010766:Phosphorylation; D011247:Pregnancy; D011270:Pregnancy, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D057134:Antibodies, Neutralizing; D005938:Glucocorticoids; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D051197:Toll-Like Receptor 4