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

Abstract

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 g/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-B (NF-B), 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-B 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-1␤, IL-6, TNF-␣, and IFN-␥), 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 prostaglandinproducing enzyme called lipocalin-prostaglandin D 2 synthase in nearterm 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.reproduction; cytokine; nuclear factor-B; extracellular signal-regulated kinase 1/2; signal transducer and activator of transcription 5

Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats

“…Our data agree with another recent study that observed significantly higher plasma levels of IL-1ra in pregnant rats at day 20 of pregnancy, vs. nonpregnant cycling rats, 4 h after intraperitoneal injection of LPS (20). However, our data appear to be somewhat contradictory to another study that demonstrated similar plasma levels of IL-1ra in rats near term of pregnancy (day 22) vs. day 15 pregnant or lactating rats 2 h after injection of LPS (day 22 pregnant rats showed attenuated febrile responses to LPS, whereas day 15 pregnant and lactating rats showed LPS-induced febrile responses that were similar to those observed in cycling females) (47). The difference between their findings and our findings is most likely due to the earlier time point after LPS administration examined (2 h compared with 4 h in our study) and/or to the different control animals used.…”

“…Mouihate et al (46) reported that COX-2 expression was reduced in pregnant rat dams on day 22 of pregnancy vs. day 15 pregnant dams, and lactating females 5 days after parturition, 3 h after LPS injection (46). Subsequently, the same group reported that the changes in COX-2 protein expression observed near term are not modulated at the transcription factor level (47), suggesting that it is most likely a mechanism upstream of COX-2, perhaps at the level of IL-1␤ activity. Having observed significant increases in plasma levels of the anti-inflammatory cytokine IL-1ra in female vs. male rats after LPS, we hypothesized that the physiological state of the female (i.e., pregnant vs. nonpregnant) may also influence plasma levels of IL-1ra.…”

“…The difference between their findings and our findings is most likely due to the earlier time point after LPS administration examined (2 h compared with 4 h in our study) and/or to the different control animals used. Mouihate et al (47) selected day 15 pregnant dams and lactating females as controls, rather than cycling females, based on their previous work indicating that febrile responses to LPS are modulated by ovarian hormones throughout the estrous cycle (48). Although this is valid, we were aiming to investigate whether the physiological state of the female (i.e., pregnant vs. nonpregnant) affects plasma levels of IL-1ra (having shown that gender modulates plasma levels of this cytokine).…”

“…However, although this would seem feasible, there have been contradictory reports in the literature regarding the importance of this anti-inflammatory cytokine after exposure of pregnant rats to LPS. One study reported increased expression of IL-1ra in pregnant vs. cycling female rats (20), whereas another observed comparable plasma levels of this cytokine in dams at different stages of pregnancy vs. lactating dams (47). In addition, it is unclear whether the attenuation of febrile responses observed near term is a physiological adaptation that is specific to pregnancy or whether differences also exist in the febrile responses to LPS in female vs. male rats.…”

Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide

“…There is evidence that NO can inhibit both the expression (12,35) and activity of COX-2 (20); conversely, others have shown an upregulation (41). First, elevated NO-cGMP signaling increases expression of IB (36), an inhibitor of NFB, thereby causing an inhibition of NFBmediated induction of COX-2 (12).…”