Suppression of the febrile response in late gestation: evidence, mechanisms and outcomes.

Fever is a beneficial host defence response. However, fever caused by the immune stimulant, lipopolysaccharide (LPS), are attenuated in many species during pregnancy, particularly near term. A number of parallel mechanisms may be responsible, and these vary in magnitude according to the time of gestation, type of inflammatory stimulus and species of animal. Some studies report a reduction in the plasma levels of circulating pro-inflammatory cytokines such as tumour necrosis factor-alpha, interleukin-1beta and interleukin-6 along with increased levels of anti-inflammatory cytokines such as interleukin-1 receptor antagonist. Associated with the attenuated febrile response to LPS is a reduction in the activation of the prostaglandin synthesising enzyme, cyclo-oxygenase 2, resulting in reduced levels of the obligatory prostaglandin mediators of the febrile response in the brain. There is also a reduction in the sensitivity of the brain to the pyrogenic action of prostaglandins, which does not appear to be due to a change in the levels of hypothalamic EP3 prostaglandin receptors. The suppression of fever at term may be important for the health of the neonate because fever in pregnant mothers may be harmful to the late-term foetus and neonate.

Neonatal inflammation produces selective behavioural deficits and alters N-methyl-D-aspartate receptor subunit mRNA in the adult rat brain.

Peripheral inflammation causes production of central cytokines that alter transmission at the N-methyl-D-aspartate receptor (NR). During development, NRs are important for synaptic plasticity and network connectivity. We therefore asked if neonatal inflammation would alter expression of NRs in the brain and behavioural performance in adulthood. We gave lipopolysaccharide (LPS) (100 microg/kg, i.p.) or saline to male rats on postnatal day (P)5, P14, P30 or P77. Subsequently we assessed mRNA levels of the NR1, NR2A, B, C and D subunits in the hippocampus and cortex either acutely (2 h) or in adulthood using real-time reverse transcriptase-polymerase chain reaction. We explored learning and memory behaviours in adult rats using the Morris water maze and contextual fear conditioning paradigms. Hippocampal NR1 mRNA was acutely increased in the P5- and P77-treated rats but was reduced in adults treated with LPS at P5, P30 and P77. P14 LPS-treated rats showed few acute changes but showed pronounced increases in NR2A, B, C and D subunit mRNA later in adulthood. The cortex displayed relatively few acute changes in expression in the neonatal-treated rats; however, it showed robust changes in NR2B, C and D mRNA in all groups given LPS in adulthood. Behavioural deficits were observed specifically in the P5 and P30 LPS-treated groups in the water maze probe trial and fear conditioning tests, consistent with hippocampal NR1 mRNA down-regulation. Thus, a single bout of inflammation during development can programme specific and persistent differences in NR mRNA subunit expression in the hippocampus, which could be associated with behavioural and cognitive deficits in adulthood.

Attenuation of fever at near term: is interleukin-6-STAT3 signalling altered?

Pregnant rats in late gestation show a reduced fever response after stimulation with lipopolysaccharide (LPS). This can result from either an increased action of endogenous antipyretics or a reduction in the production or action of endogenous pyrogens. Nonpregnant rats given LPS release interleukin (IL)-6, which causes nuclear translocation of the signal transducer and activator of transcription 3 (STAT3) in the vascular organ of the lamina terminalis (OVLT), followed by a significant increase in core body temperature. The present study investigated whether the reduced fever response in near-term pregnant rats is associated with a reduced nuclear STAT3 response. Rats at gestation day 15 (G15), gestation day 21 (G21, near term) and at lactation day 5 (L5) were injected with LPS (50 microg/kg, i.p.) or vehicle. Only near-term pregnant rats responded with an attenuated body temperature during the fever response. Immunohistological analysis indicated no significant difference in nuclear STAT3 in the OVLT of the different animal groups 2 h after LPS. Measurement of total and phosphorylated STAT3 protein in the OVLT with semiquantitative western blot revealed no significant differences of this protein among these immune challenged animal groups. IL-6 concentrations were also similar at G15, G21 and L5 2 h after injection of LPS. These results lead to the conclusion that the attenuation of the fever response at near-term pregnancy is not associated with a reduced amount of nuclear STAT3 in the OVLT, indicating a maintained IL-6-STAT3 signalling pathway in the OVLT.

Fever suppression in near-term pregnant rats is dissociated from LPS-activated signaling pathways.

Near-term pregnant rats show a suppressed fever response to LPS that is associated with reduced induction of cyclooxygenase (COX)-2 in the hypothalamus. The objective of this study is to explore whether the LPS-activated signaling pathways in the fever-controlling region of the hypothalamus are specifically altered at near term. Three rat groups consisting of 15-day pregnant rats, near-term 21- to 22-day pregnant rats, and day 5 lactating rats were injected with a febrile dose of LPS (50 mug/kg ip). The hypothalamic preoptic area and the organum vasculosum of the lamina terminalis (OVLT) were collected 2 h after LPS injection. The activation of three transcription modulators, nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase 1/2 (ERK1/2), and signal transducer and activator of transcription 5 (STAT5), was assessed using semiquantitative Western blot analysis. LPS activated the NF-kappaB pathway in all rat groups, and this response was not altered at near term. ERK1/2 and STAT5 were constitutively activated during all reproductive stages, and their levels were not significantly affected by LPS injection. Plasma levels of the proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha, and IFN-gamma), anti-inflammatory cytokines (IL-4, IL-10, and IL-1 receptor antagonist), and corticosterone were unaffected during the three reproductive stages after LPS challenge. We observed a sharp decrease in the expression of a prostaglandin-producing enzyme called lipocalin-prostaglandin D2 synthase in near-term pregnant and lactating rats. Thus fever suppression at near term is not due to an alteration in either LPS-activated intracellular signaling pathways or LPS-induced pro- and anti-inflammatory cytokine production.