Effects of endogenous glucocorticoid secretion on the interleukin-6 response to bacterial endotoxin in pregnant and non-pregnant rats

Abstract

Glucocorticoids (GCs) are released in response to immune activation by the bacterial endotoxin, lipopolysaccharide (LPS). However, GC secretion in response to immune activation and other stressors is attenuated at term of pregnancy. GCs are important modulators of the immune response, and both pro-and anti-inflammatory effects are described. Here, we examined whether GC secretion in response to LPS is maintained in earlier pregnancy before term, and investigated the role of endogenous GCs in modulating LPS-induced circulating cytokines, interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), in pregnant compared to non-pregnant female rats. Plasma corticosterone (Cort) and ACTH responses to LPS were well maintained in pregnant rats at embryonic days 15/16 (E15/16) and E18/19 compared to non-pregnant rats. At E19, maternal LPS administration increased fetal plasma Cort and decreased testosterone in male fetuses. In non-pregnant animals, pretreatment with the GC synthesis inhibitor, metyrapone, inhibited the LPS-induced increase in IL-6, and the IL-6 response was restored by Cort replacement, indicating that LPS induction of IL-6 is Cort-dependent. In E15 pregnant animals, metyrapone had no effect on LPS-induced IL-6 levels, indicating that LPS-induction of IL-6 is not dependent on Cort. These contrasting patterns of IL-6 induction in nonpregnant and pregnant animals were reflected in levels of hypothalamic Socs3 mRNA, an indicator of IL-6 signaling pathway activation. In both non-pregnant and pregnant rats, LPS-induced plasma TNF-a responses were inhibited by metyrapone but not re-instated by Cort replacement. It is suggested that altered GC regulation of IL-6 may be required to sustain specialized functions of IL-6 during pregnancy.

Dehydroepiandrosterone and metyrapone partially restore the adaptive humoral and cellular immune response in endotoxin immunosuppressed mice

“…55 However, other researchers have described an inhibition of LPSinduced TNF-a by MET. 56 With these last results in mind, some authors have suggested that an enzyme of the cytochrome P450 family might be involved in the signaling pathway leading to TNF-a production. This would be another effect of MET administration apart from the already described blockade of glucocorticoids (GC) synthesis.…”

Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route‐based learning as a function of maternal body weight gain after prenatal exposure to poly IC

“…Many of these studies have been done in mice. While there is a somewhat smaller literature in rats there is a related literature on prenatal LPS in rats, e.g., (Romero et al, 2007;Harvey and Boksa, 2011;Nouel et al, 2011;Cui et al, 2009;Cui et al, 2011;Ashdown et al, 2006;Fortier et al, 2007;Fortier et al, 2004a) supporting the connection between prenatal immune activation and adverse effects on brain development in the progeny.…”

Sticanje i pozivanje prostorne memorije kod potomstva zenki pacova izlozenih lipopolisaharidom izazvanom zapaljenju tokom trudnoce

“…Primena LPS-a i uzimanje krvi gravidnim ženkama Gravidnim ženkama pacova (n = 8 po tretmanu), telesne mase između 300 i 400 g, jednom dnevno je, intraperitonealnim putem, primenjivano 100 µg/kg lipopolisaharida (LPS), komponente ćelijskog zida Gram negativnih bakterija (serotip LPS-a iz bakterije Escherichia coli 0111:B4, Sigma, Nemačka) koji smo rastvorili u fiziološkom rastvoru (LPS grupa), ili 1 ml/kg sterilnog fiziološkog rastvora (SAL grupa), i to 15. i 16. dana gestacije [7] između 10 h i 12 h. Gravidnim ženkama je 15. dana gestacije dva sata nakon tretmana (LPS ili SAL) uzimana krv iz repne vene heparinizovanim "leptir" infuzionim sistemom, koja je potom preneta u heparinizovane ependorfice. Prikupljeni uzorci krvi su centrifugirani 10 minuta na 5000 g i temperaturi od 4°C.…”