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¹ Department of Physiology & Biophysics, University of Calgary, Health Sciences Centre, 3330 Hospital Drive, NW Calgary, Alberta, Canada T2N 4 N1

	Abstract

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Rats have an attenuated febrile response to intraperitoneal (I.P.) administration of exogenous pyrogen (e.g. bacterial endotoxin) near the term of pregnancy. To investigate possible mechanisms of this unique thermoregulatory response, the present experiments were carried out on 18 non-pregnant and 16 near-term pregnant Sprague-Dawley rats to test the hypothesis that pregnancy alters the balance of pyrogenic cytokines and antipyretic and/or cryogenic (antipyretic/cryogenic) cytokines in response to exogenous pyrogen. To test our hypothesis, we measured plasma levels of interleukin (IL)-1ß, IL-6, interleukin-1 receptor antagonist (IL-1ra) and tumour necrosis factor (TNF) at 2 and 4 h following I.P. administration of 160 µg kg^–1 E. coli lipopolysaccharide (LPS) (i.e. EC₁₀₀ dose, or the smallest dose that elicits a maximal febrile response in non-pregnant rats) in non-pregnant as well as pregnant rats at day 20 of gestation (term 21 days). In non-pregnant rats, E. coli LPS elicited statistically significant increases in plasma concentrations of IL-1ß, IL-6, IL-1ra and TNF as compared to that observed following administration of vehicle. However in pregnant rats, E. coli LPS elicited statistically significant increases in antipyretic/cryogenic cytokines (IL-1ra and TNF) but not in pyrogenic cytokines (IL-1ß and IL-6). Thus, a differential pyrogenic and antipyretic/cryogenic plasma cytokine response may mediate in part the attenuated febrile response to exogenous pyrogen observed in rats near the term of pregnancy.

(Received 7 July 2004; accepted after revision 21 September 2004; first published online 4 October 2004)
Corresponding author J. E. Fewell: Heritage Medical Research Building, 206, University of Calgary, 3330 Hospital Drive, NW Calgary, Alberta, Canada T2N 4 N1. Email: fewell{at}ucalgary.ca

	Introduction

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Numerous physiological changes occur during the maternal adaptation to pregnancy including reversible alterations in the regulation of core temperature. In pregnant rats, for example, basal core temperature decreases as much as 0.8°C from day 10 of gestation to term (i.e. day 21 of gestation) and then increases rapidly following parturition (Fewell, 1995). Furthermore, rats have attenuated core temperature responses to exogenous pyrogen (Martin et al. 1995; Fofie & Fewell, 2003), endogenous pyrogen (Simrose & Fewell, 1995) and E-series prostaglandins (Stobie-Hayes & Fewell, 1996; Eliason & Fewell, 1997), as well as to psychological ‘stress’ (Fewell & Tang, 1997) near the term of pregnancy compared to those observed early in gestation or in the non-pregnant state. The mechanism(s) and consequences of these pregnancy-induced changes in thermoregulatory control are presently unknown.

Since the early work of Milton & Wendlandt (1970), prostaglandins of the E-series have been thought to play an important role in the central nervous system orchestration of heat-producing and heat-conserving mechanisms to effect an increase in core temperature following exposure to blood-borne pyrogen. Depending upon concentration and perhaps species, a blood-borne pyrogen is thought to evoke the synthesis and release from the central nervous system of E-series prostaglandins via multiple routes including passage into the brain at circumventricular organs such as the organum vasculosum laminae terminalis (OVLT) (Blatteis et al. 1983; Stitt, 1985; Katsuura et al. 1990), via barrier cell-mediated pathways (van Dam et al. 1996; Cao et al. 1996), by stimulation of vagal afferents (Watkins et al. 1995) and by active transport mechanisms (Banks et al. 1989; Banks & Kastin, 1991). We have recently shown that release of E-series prostaglandins into the interstitial fluid surrounding the OVLT is decreased in pregnant rats on days 19, 20 and 21 of gestation compared to that observed in non-pregnant rats following intravenous administration of recombinant rat interleukin (IL)-1ß (Fewell et al. 2002). We postulated that this was secondary to a pregnancy-related increase in circulating levels of interleukin-1 receptor antagonist (IL-1ra) similar to that observed in humans near the term of pregnancy (Pillay et al. 1993). IL-1ra is produced by monocytes and other cell types, released into plasma together with cytokines such as IL-1 and IL-1ß (Arend, 1991) and competes with these cytokines for occupancy of type I and type II interleukin receptors on a variety of cells, and hence may alter the end-organ response such as synthesis and release of E-series prostaglandins in the central nervous system.

Subsequently, we found that neither basal plasma concentrations of IL-1ra nor the ratio of IL-1ra to IL-1ß were increased on day 20 of gestation as compared to that measured in non-pregnant rats (Fofie & Fewell, 2003). However, our results do not preclude the possibility that pregnancy influences the synthesis and release of IL-1ra relative to IL-1ß following exposure to blood-borne pyrogen. Given that the core temperature response following administration of exogenous pyrogen probably results from the interaction of pyrogenic (IL-1ß and IL-6) and antipyretic/cryogenic (IL-1ra and TNF) cytokines (Kluger, 1991), the aim of our current experiments has been to test the hypothesis that pregnancy alters the balance of pyrogenic and antipyretic/cryogenic cytokines in response to exogenous pyrogen. To test our hypothesis, we have measured plasma levels of IL-1ß, IL-6, IL-1ra and TNF following I.P. administration of E. coli LPS in non-pregnant as well as in near-term pregnant rats.

	Methods

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Experiments were carried out on 18 non-pregnant and 16 pregnant Sprague-Dawley rats (Charles River Laboratories) undergoing their first pregnancy, and weighing an average 199 ± 18 g (non-pregnant) and 275 ± 12 g (day 20) at the time of experiment. Rats were housed individually in Plexiglas cages containing Aspen-Chip laboratory bedding (North-eastern Products) which were kept in a humidity- (30–40%) and temperature-controlled environmental chamber held at 25 ± 1°C on a 12 : 12 h light–dark cycle with lights on from 07.00 h. Rats were handled several times and exposed to the laboratory surroundings – including the guillotine used for decapitation – several times prior to an experiment. All animals had continuous access to food (Laboratory Diet 5001) and tap water.

All surgical and experimental procedures were carried out in accordance with the Guide to the Care and Use of Experimental Animals provided by the Canadian Council on Animal Care and with the approval of the Animal Care Committee of the University of Calgary.

Surgical preparation

No less than 3 days prior to an experiment, each rat was anaesthetized by inhalation of halothane (2% for induction and maintenance) in oxygen. A paramedian laparotomy was performed and the tip of a sterile catheter of silicone tubing (Dow Corning Silastic; Helix Medical Inc.) was placed in the peritoneal cavity for later administration of injectate; the remainder of the catheter was tunnelled under the skin and exteriorized at the dorsal scapular area. We have previously shown that I.P. drug administration via a chronically implanted catheter does not elicit ‘stress-induced hyperthermia’ in non-pregnant female rats as normally occurs when one pierces the abdominal wall with a needle for drug administration (Dymond & Fewell, 1998). Muscle and skin layers were sutured to close the incisions, and the catheter was secured in place with a purse-string suture and tissue adhesive (Vetbond; 3M). Topical antibiotic spray (Topazone; Austin) and spray adhesive bandage (OpSite; Smith&Nephew) were applied to all wounds.

Experimental protocol

Non-pregnant (N) and pregnant rats at day 20 of gestation (P) were each allocated to four experimental groups based upon injection of vehicle (V) or 160 µg kg^–1 E. coli LPS (LPS) and blood sampling times relative to the injection (2 h or 4 h): NP V 2 h (n = 4); NP V 4 h (n = 5); NP LPS 2 h (n = 4); NP LPS 4 h (n = 5); and P V 2 h (n = 4); P V 4 h (n = 4); P LPS 2 h (n = 4); P LPS 4 h (n = 4). In previous experiments, we determined an E. coli LPS dose of 160 µg/ kg^–1 to be the EC₁₀₀ (i.e. the minimal dose that produced a maximal core temperature response), based upon I.P. E. coli LPS dose–fever index (Cooper et al. 1979) response experiments in non-pregnant rats (Fofie & Fewell, 2003); the current experiments were carried out under identical conditions using the same experimental setup, stock solution and dose of pyrogen (Escherichia coli Serotype 0111:B4, Lot 31K4121, Sigma, St Louis, MO, USA). Blood sampling times were based upon previous core temperature–time plots of non-pregnant and pregnant animals following an EC₁₀₀ dose of E. coli LPS (Fofie & Fewell, 2003). At 2 h following an EC₁₀₀ dose of E. coli LPS, non-pregnant rats display early generation of fever whereas near-term pregnant rats display hypothermia. At 4 h following an EC₁₀₀ dose of E. coli LPS, the fever reached a plateau in non-pregnant rats whereas the core temperature of pregnant rats returns to control levels following the early period of hypothermia.

On the day prior to an experiment, each animal was removed from its cage, weighed, and then returned to its cage in the environmental chamber. On the day of an experiment, the rat was given an I.P. injection of vehicle or E. coli LPS in its cage. The rats remained in their cage until trunk blood was collected at 2 or 4 h following rapid decapitation using a guillotine. Trunk blood was collected on ice in centrifuge tubes containing EDTA, aprotinin and indomethacin (Cannon et al. 1988). The blood was centrifuged at 4°C for 10 min and the resulting plasma was stored at –70°C until IL-1ß, IL-6, IL-1ra and TNF concentrations were determined in duplicate by enzyme-linked immunosorbent assay (ELISA) (BioSource: IL-1ß sensitivity, < 3 pg ml^–1; IL-6 sensitivity, < 10 pg ml^–1; IL-1ra, sensitivity < 12 pg ml^–1; R & D: TNF sensitivity, < 5 pg ml^–1). All experiments were carried out during the light cycle and began between 10.00 h and 11.00 h to avoid any circadian effects on the measured variables.

Statistical analysis

Statistical analysis was carried out using an analysis of variance followed by a Newman–Keuls multiple comparison test in order to determine if pregnancy (non-pregnant, day 20 gestation), injection (vehicle, 160 µg/kg E. coli LPS) or time (2 h, 4 h) influenced plasma concentrations of IL-1ß, IL-6, IL-1ra or TNF. All results are reported as means ± one standard deviation; P < 0.05 was considered to be of statistical significance.

	Results

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In non-pregnant rats, I.P. administration of 160 µg kg^–1 E. coli LPS elicited statistically significant increases in plasma concentrations of IL-1ß (Fig. 1), IL-6 (Fig. 2), IL-1ra (Fig. 3) and TNF (Fig. 4) as compared to the concentrations observed following I.P. administration of vehicle. It is interesting that plasma concentrations of IL-1ß and IL-1ra were increased significantly at 2 and 4 h following I.P. administration of 160 µg kg^–1 E. coli LPS whereas plasma concentrations of IL-6 and TNF were increased significantly only at 2 h post injection.

View larger version (16K): [in this window] [in a new window]   Figure 1.  Plasma concentrations of IL-1ß Plasma concentrations of IL-1ß in non-pregnant (n = 18) and pregnant rats on day 20 of gestation (n = 16) collected at 2 and 4 h after injection of vehicle (Veh) or 160 µg kg–1E. coli LPS (LPS). *P < 0.05 versus Veh at equivalent sample time in non-pregnant rats; #P < 0.05 versus LPS at equivalent sample time in non-pregnant rats.

View larger version (16K): [in this window] [in a new window]   Figure 2.  Plasma concentrations of IL-6 Plasma concentrations of IL-6 in non-pregnant (n = 18) and pregnant rats on day 20 of gestation (n = 16) collected at 2 and 4 h after injection of vehicle (Veh) or 160 µg kg–1E. coli LPS (LPS). *P < 0.05 versus Veh at equivalent sample time in non-pregnant rats; #P < 0.05 versus LPS at equivalent sample time in non-pregnant rats.

View larger version (18K): [in this window] [in a new window]   Figure 3.  Plasma concentrations of IL-1ra Plasma concentrations of IL-1ra in non-pregnant (n = 18) and pregnant rats on day 20 of gestation (n = 16) collected at 2 and 4 h after injection of vehicle (Veh) or 160 µg kg–1E. coli LPS (LPS). *P < 0.05 versus Veh at equivalent sample time in rats of same pregnancy status; #P < 0.05 versus LPS at equivalent sample time in non-pregnant rats.

View larger version (15K): [in this window] [in a new window]   Figure 4.  Plasma concentrations of TNF Plasma concentrations of TNF in non-pregnant (n = 18) and pregnant rats on day 20 of gestation (n = 16) collected at 2 and 4 h after injection of vehicle (Veh) or 160 µg kg–1E. coli LPS (LPS). *P < 0.05 versus Veh at equivalent sample time in rats of same pregnancy status; #P < 0.05 versus LPS at equivalent sample time in non-pregnant rats.

	Discussion

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Our experiments provide new information about possible mechanisms of the attenuated febrile response observed following I.P. administration of exogenous pyrogen in rats near the term of pregnancy (Martin et al. 1995; Fofie & Fewell, 2003). A novel finding in our study was that I.P. administration of 160 µg kg^–1 E. coli LPS (i.e. EC₁₀₀) elicited statistically significant increases in plasma concentrations of pyrogenic cytokines (IL-1ß and IL-6) and antipyretic/cryogenic cytokines (IL-1ra and TNF) in non-pregnant but not in pregnant rats. In pregnant rats, LPS elicited statistically significant increases in IL-1ra and TNF but not IL-1ß and IL-6. Given that the core temperature response following administration of exogenous pyrogen probably results from the balance of pyrogenic and antipyretic/cryogenic cytokines (Kluger, 1991), our data provide evidence that a differential pyrogenic and antipyretic/cryogenic plasma cytokine response mediates at least in part the attenuated febrile response to exogenous pyrogen observed in rats near the term of pregnancy (Martin et al. 1995; Fofie & Fewell, 2003).

We previously reported that I.P. administration of E. coli LPS to non-pregnant Sprague-Dawley rats in doses ranging from 1 to 1280 µg kg^–1 elicits an increase in the fever index – which estimates overall heat gain or heat loss during an experiment – as compared to vehicle with an EC₅₀ of 20 µg kg^–1 and an EC₁₀₀ of 160 µg kg^–1 (Fofie & Fewell, 2003). Following I.P. administration of 160 µg kg^–1 E. coli LPS, non-pregnant rats mount a core temperature response with a latency, magnitude and duration of 1.5 h, 1.9°C and at least 4.5 h, respectively. However in pregnant rats, this same dose of E. coli LPS elicits a distinct period of hypothermia with a latency, magnitude and duration of 0.5 h, –1.2°C and 2.5 h, respectively, before mounting a modest febrile response at 5.5 h post injection. Our current results provide evidence that this initial period of hypothermia occurs at a time when the antipyretic/cryogenic cytokines IL-1ra and TNF are unopposed by the pyrogenic cytokines IL-1ß and IL-6. Furthermore, the fact that core temperature and plasma concentrations of TNF return to control levels by 4 h despite the continued elevated plasma concentration of IL-1ra would allow one to speculate that it is primarily TNF that mediates the early hypothermia associated with this relatively large dose of LPS in near-term pregnant animals. This postulate is in keeping with previous results showing the association of hypothermia and early increases in TNF following LPS administration in male rats (Tollner et al. 2000; Dogan et al. 2000, 2002), and that inhibition of TNF attenuates the hypothermic response to LPS in rats (Derijk & Berkenbosch, 1994; Tollner et al. 2000). Waage (1987) has shown that TNF is released into the circulation of rats as a burst in response to LPS with a maximum serum concentration of TNF occurring at 60–90 min. Furthermore, he has shown that TNF is eliminated from the serum according to first order kinetics with a calculated half-life of 27 ± 7 min.

The attenuated pyrogenic cytokine response and accentuated antipyretic/cryogenic cytokine response to LPS may result from the unique hormonal changes that occur near the term of pregnancy in rats. Some of these hormonal changes include a decrease in serum progesterone levels (Pepe & Rothchild, 1974) and an increase in serum oestradiol (Shaikh, 1971) and corticosterone levels. Progesterone has long been known to have thermogenic effects (Nieburgs & Greenblatt, 1948; Freeman et al. 1970) and has recently been shown to influence firing patterns of preoptic thermosensitive neurones (Nakayama et al. 1975). Progesterone levels decrease dramatically from day 19 to term of gestation in rats and therefore may influence basal core temperature as well as the core temperature response to perturbation (Morishige et al. 1973). This premise requires further investigation. Perhaps more likely candidates are the glucocorticoids, including corticosterone, as they are known to modulate fever in rats following exposure to LPS (Morrow et al. 1993). Glucocorticoids are anti-inflammatory and modulate various aspects of the inflammatory process by influencing gene transcription and resulting protein synthesis (Barnes, 1998). For example, they have been shown to repress the cellular production of IL-1ß by inhibiting transcription of the IL-1ß gene and to decrease the stability of IL-1ß mRNA (Knudsen et al. 1987; Lew et al. 1988; Lee et al. 1988). Furthermore, glucocorticoids have been shown to induce the synthesis of IL-1ra (Levine et al. 1996), which blocks binding of IL-1 to its receptors, and to induce the synthesis of the decoy IL-1 surface receptor – IL-1R2 – thus reducing the functional activity of IL-1. Thus, it is likely that glucocorticoids, via multiple mechanisms, play a major role in altering the balance of pyrogenic cytokines and antipyretic/cryogenic cytokines in response to exogenous pyrogen and in mediating the attenuated febrile response near the term of pregnancy. This is currently under investigation in our laboratory.

In summary, our experiments provide evidence that pregnancy influences the cytokine response to exogenous pyrogen with a predominant antipyretic/cryogenic cytokine response relative to a pyrogenic response near the term of gestation. It is likely that this differential cytokine response plays a major role in mediating the unique thermoregulatory response of near-term pregnant rats to a relatively large dose of exogenous pyrogen (Martin et al. 1995; Fofie & Fewell, 2003).

	References

Top Abstract Introduction Methods Results Discussion References

 
Arend WP (1991). Interleukin-1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest 88, 1445–1451.

Banks WA & Kastin AJ (1991). Blood to brain transport of interleukin links the immune and central nervous systems. Life Sci 48, PL117–PL121.[CrossRef][Medline]

Banks WA, Kastin AJ & Durham DA (1989). Bidirectional transport of interleukin-1 alpha across the blood–brain barrier. Brain Res Bull 23, 433–437.[CrossRef][Medline]

Barnes PJ (1998). Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci 94, 557–572.[Medline]

Blatteis CM, Bealer SL, Hunter WS, Llanos QJ, Ahokas RA & Mashburn TA Jr (1983). Suppression of fever after lesions of the anteroventral third ventricle in guinea pigs. Brain Res Bull 11, 519–526.[CrossRef][Medline]

Cannon JG, van der Meer JWM, Kwiatkowski D, Endres S, Lonnemann G, Burke JF & Dinarello CA (1988). Interleukin-1ß in human plasma: optimization of blood collection, plasma extraction, and radioimmunoassay methods. Lymphokine Res 7, 457–467.[Medline]

Cao C, Matsumura K, Yamagata K & Watanabe Y (1996). Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. Brain Res 733, 263–272.[CrossRef][Medline]

Cooper KE, Kasting NW, Lederis K & Veale WL (1979). Evidence supporting a role for endogenous vasopressin in natural suppression of fever in the sheep. J Physiol 295, 33–45.[Abstract/Free Full Text]

Derijk RH & Berkenbosch F (1994). Hypothermia to endotoxin involves the cytokine tumor necrosis and the neuropeptide vasopressin in rats. Am J Physiol 266, R9–R14.

Dogan MD, Ataoglu H & Akarsu ES (2000). Effects of different serotypes of Escherichia coli lipopolysaccharide on body temperature in rats. Life Sci 67, 2319–2329.[CrossRef][Medline]

Dogan MD, Ataoglu H & Akarsu ES (2002). Characterization of the hypothermic component of LPS-induced dual thermoregulatory response in rats. Pharmacol Biochem Behav 72, 143–150.[CrossRef][Medline]

Dymond KE & Fewell JE (1998). Coordination of autonomic and behavioral thermoregulatory responses during exposure to a novel stimulus in rats. Am J Physiol 275, R673–R676.

Eliason HL & Fewell JE (1997). Influence of pregnancy on the febrile response to ICV administration of PGE₁ in rats studied in a thermocline. J Appl Physiol 82, 1453–1458.[Abstract/Free Full Text]

Fewell JE (1995). Body temperature regulation in rats near term of pregnancy. Can J Physiol Pharmacol 73, 364–368.[Medline]

Fewell JE, Eliason HL & Auer RN (2002). Peri-OVLT E-series prostaglandins and core temperature do not increase following intravenous IL-1b in pregnant rats. J Appl Physiol 93, 531–536.[Abstract/Free Full Text]

Fewell JE & Tang PA (1997). Pregnancy alters body-core temperature response to a simulated open field in rats. J Appl Physiol 82, 1406–1410.[Abstract/Free Full Text]

Fofie AE & Fewell JE (2003). Influence of pregnancy on plasma cytokines and the febrile response to intraperitoneal administration of bacterial endotoxin in rats. Exp Physiol 88, 747–754.[Abstract]

Freeman ME, Crissman JK, Louw GN, Butcher RL & Inskeep EK (1970). Thermogenic action of progesterone in the rat. Endocrinology 86, 717–720.[Medline]

Katsuura G, Arimura A, Koves K & Gottschall PE (1990). Involvement of organum vasculosum of laminia terminalis and preoptic area in interleukin 1ß-induced ACTH release. Am J Physiol 258, E163–E171.

Kluger MJ (1991). Fever: role of pyrogens and cryogens. Physiol Rev 71, 93–127.[Abstract]

Knudsen PJ, Dinarello CA & Strom TB (1987). Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol 139, 4129–4134.[Abstract]

Lee SW, Tsou AP, Chan H, Thomas J, Petrie K, Eugui EM & Allison AC (1988). Glucocorticoids selectively inhibit the transcription of the interleukin 1ß gene and decrease the stability of interleukin 1ß mRNA. Immunology 85, 1204–1208.

Levine SJ, Benfield T & Shelhamer JH (1996). Corticosteroids induce intracellular interleukin-1 receptor antagonist type 1 expression by a human airway epithelial cell line. Am J Respir Cell Mol Biol 15, 245–251.[Abstract]

Lew W, Oppenheim JJ & Matsusuhima K (1988). Analysis of the suppression of IL-1alpha and IL-1beta production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone. J Immunol 140, 1895–1902.[Abstract/Free Full Text]

Martin SM, Malkinson TJ, Veale WL & Pittman QJ (1995). Fever in pregnant, parturient, and lactating rats. Am J Physiol 268, R919–R923.

Milton AS & Wendlandt S (1970). A possible role for prostaglandin E1 as a modulator for temperature regulation in the central nervous system of the cat. J Physiol 207, 76P–77P.

Morishige WK, Pepe GJ & Rothchild I (1973). Serum luteinizing hormone, prolactin and progesterone levels during pregnancy in the rat. Endocrinology 92, 1527–1530.[Medline]

Morrow LE, McClellan JL, Conn CA & Kluger MJ (1993). Glucocorticoids alter fever and IL-6 responses to psychological stress and to lipopolysaccharide. Am J Physiol 264, R1010–R1016.

Nakayama T, Suzuki M & Ishizuka N (1975). Action of progesterone on preoptic thermosensitive neurones. Nature 258, 80.[Medline]

Nieburgs HE & Greenblatt RB (1948). The role of the endocrine glands in body temperature regulation. J Clin Endocrinol 8, 622–623.

Pepe GJ & Rothchild I (1974). A comparative study of serum progesterone levels in pregnancy and various types of pseudopregnancy in the rat. Endocrinology 95, 275–279.[Medline]

Pillay V, Savage N & Laburn H (1993). Interleukin-1 receptor antagonist in newborn babies and pregnant women. Pflugers Arch 424, 549–551.[CrossRef][Medline]

Shaikh AA (1971). Estrone and estradiol levels in ovarian blood from rats during the estrous cycle and pregnancy. Biol Reprod 5, 297–307.[Abstract]

Simrose RL & Fewell JE (1995). Body temperature response to IL-1b in pregnant rats. Am J Physiol 38, R1179–R1182.

Stitt JT (1985). Evidence for the involvement of the organism vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol 368, 501–511.[Abstract/Free Full Text]

Stobie-Hayes KM & Fewell JE (1996). Influence of pregnancy on the febrile response to intracerebroventricular administration of PGE1 in rats. J Appl Physiol 81, 1312–1315.[Abstract/Free Full Text]

Tollner B, Roth J, Storr B, Martin D, Voigt K & Zeisberger E (2000). The role of tumor necrosis factor (TNF) in the febrile and metabolic responses of rats to intraperitoneal injection of a high dose of lipopolysaccharide. Pflugers Arch 440, 925–932.[CrossRef][Medline]

van Dam AM, de Vries HE, Kuiper J, Zijlstra FJ, de Boer AG, Tilders FJH & Berkenbosch F (1996). Interleukin-1 receptors on rat brain endothelial cells: a role in neuroimmune interaction? FASEB J 10, 351–356.[Abstract]

Waage A (1987). Production and clearance of tumor necrosis factor in rats exposed to endotoxin and dexamethasone. Clin Immunol Immunopathol 45, 348–355.[CrossRef][Medline]

Watkins LR, Goehler LE, Relton JK, Tartaglia N, Silbert L, Martin D & Maier SF (1995). Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett 183, 27–31.[CrossRef][Medline]

	Acknowledgements

 
The authors would like to thank Mrs Donna Farley for carrying out the cytokine assays. This study was supported by the Canadian Institutes of Health Research.

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