Aims: 

In several mammals, including rats, the febrile response to the neuroimmune stressor, lipopolysaccharide (LPS) is attenuated at near term and recovers in the post partum period. Methods:

We have carried out a series of physiological and neurochemical investigations to attempt to identify the mechanisms underlying the reduced neuroimmune response.

Results: 

Levels of pro-inflammatory cytokines (IL-1b, IL-6, IFNg, and TNFa) in the plasma taken 2h after LPS were similar at gestational day (G) 15, G22 or lactation day (L) 5 suggesting identical responses to TLR4 activation. In addition the anti-inflammatory cytokines, IL-1ra and IL-10, and the immunosuppressive hormone, corticosterone, were similar after LPS at the 3 stages of reproduction. Cytokines are known to cause fever by initiating the synthesis of prostaglandin E (PGE). To test the hypothesis that PGE synthesis or action was altered at term, we used semi-quantitative Western blots to measure levels of inducible COX-2, the rate limiting enzyme for the synthesis of PGE that is found in endothelial cells of the brain vasculature. We found that COX-2 levels in the hypothalamus are reduced at G22 compared to G15 or at L5. Pro-inflammatory cytokines activate COX-2 through a number of signaling pathways, so we explored if these were similarly altered. However, the reduced COX-2 expression was not associated with alterations in activation of transcriptional factors NFkB, STAT 3 and STAT5 or of ERK1/2.

Conclusions: 

The reduced fevers at term are associated with a reduction in PGE synthesis in the brain, but the mechanisms responsible remain elusive.