J. Anim Sci. 2006. 84:2083-2088. doi:10.2527/jas.2005-625
© 2006 American Society of Animal Science
ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
Changes in ovine maternal temperature, and serum cortisol and interleukin-6 concentrations after challenge with Escherichia coli lipopolysaccharide during pregnancy and early lactation1
L. Kabaroff*,
H. Boermans
and
N. A. Karrow*,2
* Department of Animal and Poultry Science;
and
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada, N1G 2W1
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Abstract
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Major changes in maternal physiology during pregnancy and lactation can have a large impact on the immune and neuroendocrine systems. One of the most significant changes, observed in rats and mice, is hyporesponsiveness of the hypothalamic pituitary adrenal axis (HPAA) in response to inflammation, restraint, and other psychological stressors during late pregnancy and lactation. This attenuation, however, has not been well characterized in ruminant animals and may be relevant to their susceptibility to inflammatory diseases during these periods. Thus, the intent of this study was to characterize responsiveness of the ovine HPAA to inflammatory challenge during pregnancy and lactation. Ewes from early (33 d), middle (55 d), and late (138 d) pregnancy, as well as early lactation (10 d), were challenged i.v. with a bolus dose of 400 ng of Escherichia coli lipopolysaccharide (LPS)/kg of BW or saline. A corresponding group of nonpregnant ewes was also challenged with LPS to serve as positive control animals for each pregnancy and lactation study. Responsiveness of the HPAA was assessed by measuring the 4-h change in serum cortisol concentration after LPS challenge. The cortisol increase after LPS challenge was elevated (P < 0.01) in pregnant ewes during late pregnancy over that of nonpregnant animals. In contrast, the characteristic temperature response associated with systemic LPS challenge was decreased (P < 0.01) during early pregnancy and lactation compared with nonpregnant or nonlactating animals. Serum IL-6 concentrations were measured to assess whether changes in HPAA responsiveness during pregnancy or lactation were attributed to changes in proinflammatory signaling to the HPAA. Interestingly, enhanced cortisol responsiveness during late pregnancy was correlated with increased (P < 0.01) serum IL-6 concentrations, indicating that IL-6 may contribute to enhanced HPAA responsiveness during this period. Serum IL-6 concentrations during early and midpregnancy did not increase in response to LPS challenge, indicating that HPAA activation during periods of pregnancy may be independent of IL-6 production.
Key Words: hypothalamic-pituitary-adrenal axis • lactation • lipopolysaccharide • ovine • pregnancy
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INTRODUCTION
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In recent years, our understanding of interaction between the neuroendocrine system and the immune system has greatly increased. It is well known that the hypothalamic-pituitary-adrenal axis (HPAA) is involved in maintaining basal and stress-related homeostasis and that glucocorticoids (GC) play a key role in regulating the potentially damaging host inflammatory response (Chrousos, 1995
; Pruett, 2003). Activation of the HPAA occurs during gram-negative bacterial infections by an elaborate signaling pathway that is initiated by bacterial lipopolysaccharide (LPS). The inflammatory response is initiated by the release of the proinflammatory mediators IL-1ß, IL-6, and tumor necrosis factor (TNF)-
(Takeda et al., 2003; Donn and Ray, 2004). Locally, these mediators stimulate cells to upregulate the inflammatory reaction; systemically they activate the HPAA and induce the temperature response associated with bacterial infection (Chrousos, 1992, 1995; Gabay and Kushner, 1999).
In many species, HPAA responsiveness to stress is attenuated during late pregnancy and lactation (Weinstock, 1997; Shanks et al., 1999; Neumann, 2001). Rodent studies, for example, have demonstrated HPAA attenuation in response to various types of stressors during pregnancy and lactation (Windle et al., 1997; Neumann et al., 1998; Johnstone et al., 2000). The cortisol response in lactating rats is also reduced by suckling stress (Toufexis and Walker, 1996) and endotoxin (Shanks et al., 1999), whereas sheep display decreased pituitary responsiveness to corticotrophin-releasing hormone and arginine vasopressin in vitro during late pregnancy (Young and Rose, 2001). In this study, we investigated whether the ovine HPAA response was attenuated in vivo in response to a systemic endotoxin-induced inflammatory challenge at different stages of pregnancy and during early lactation; such a response could exacerbate inflammatory tissue damage during bacterial infections.
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MATERIALS AND METHODS
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Experimental Design
The University of Guelph Animal Care Committee approved all procedures involving animals. In total, 50 pregnant, 16 lactating, and 32 nonpregnant and nonlactating Riduea-Arcott ewes were used in 4 separate studies. Sheep were challenged with an i.v. injection of LPS from Escherichia coli, serotype O111:B4 (400 ng/kg of BW; Sigma Chemical, St. Louis, MO) or saline during early (33 d), mid (55 d), and late pregnancy (138 d), as well as early lactation (10 d postpartum; Figure 1). All sheep were held at the Ontario Ministry of Agriculture and Food Ponsonby Research Station, Ontario, Canada. Animals were housed in individual pens with access to food and water ad libitum.
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Figure 1. Experimental design for the study of effects of Escherichia coli serotype O111:B4 lipopolysaccharide (LPS) in pregnant (preg; d 33, 55, and 138), lactating (lact; d 10), and nonpregnant (nonpreg) nonlactating (nonlact) sheep. Control sheep were administered saline. Numbers in parentheses represent the number of sheep in each group.
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Jugular venous blood was collected in silicon gel and clot activator Vacutainer tubes (Becton Dickinson and Company, Oakville, Ontario, Canada) at 0 and 4 h relative to LPS. Blood was allowed to clot for approximately 45 min and was then centrifuged at 1,000 x g for 15 min at room temperature. The serum was aliquoted into microcentrifuge tubes and stored at –80°C. Body temperatures were determined by measuring rectal temperatures with a standard digital thermometer.
Serum Cortisol Analysis
Free cortisol concentrations were determined in sera using a commercially available cortisol luminescence immunoassay kit according to the manufacturer’s instructions (IBL Hamburg, Minneapolis, MN). The chemiluminescent end point was read using a Victor 3 plate reader (Perkin Elmer, Wellesley, MA). Samples were analyzed in triplicate with an average intraassay CV of 6.2% for all plates.
Serum IL-6 Analysis
A sandwich ELISA was used to determine serum IL-6 concentrations. High-affinity binding, flat-bottomed, 96-well plates (Corning, Acton, MA) were coated overnight at 4°C with a monoclonal mouse anti-ovine IL-6 antibody (Serotec, Raleigh, NC) diluted 1:200 in carbonate buffer containing 1.59 g/L Na2CO3 and 2.93 g/L NaHCO (pH 9.6). After 3 washes with 100 µL of PBS and 0.5% tween (PBS-Tween; Serotec), the plates were blocked with 200 µL of Ultrablock (Serotec) for 1 h at 37°C. The wells were washed 3 times with PBS-Tween and then incubated with 100 µL of the serum samples, diluted 1:12.5 with PBS, in triplicate for 1 h at 37°C. After 3 washes with PBS-Tween, 100 µL of the primary antibody (polyclonal rabbit anti-ovine IL-6; Serotec), diluted in PBS-Tween (1:500), was added and incubated for 1 h at 37°C. The plates were washed 3 times and the secondary antibody (goat antirabbit immunoglobulin G, horseradish peroxidase; Biosource Int., Camarillo, CA), diluted 1:25,000 in PBS-Tween, was added to the wells and incubated for 1 h at 37°C. The wells were washed 4 times, and 3, 3, 5, 5-tetramethylbenzidine (TMB; Sigma Chemical, St. Louis, MO) was added at 100 µL/well for 40 min to initiate the color reaction. The reaction was stopped with 50 µL of Stop Reagent for TMB substrate (Sigma Chemical), and the plates were read at 450 nm using the Victor 3 plate reader. A serial dilution of pooled serum samples from 8 animals challenged with 400 ng of LPS/kg of BW was performed on each test plate to determine the titer of each test sample. Samples were performed in triplicate, with an average intraassay CV of 7% for all plates. All samples were run in a single assay.
Statistical Analysis
Statistical analysis was performed on the 4-h change in temperature, cortisol, and IL-6 values using GLM of SAS (SAS Inst. Inc., Cary, NC). Residual plots were examined to assess homogeneity of variance. Multiple comparisons were performed on the least squares means using the Tukey-Kramer test (P < 0.05) to determine which treatment groups were significantly different from one another. In the case of the IL-6 data, a natural log transformation was used to ensure homogeneity of variance.
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RESULTS
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During all stages of pregnancy and lactation, all LPS challenged sheep had a greater temperature response (P < 0.01) compared with the saline control group, indicating that they all responded to LPS challenge (Figure 2). Basal body temperatures were not significantly different between pregnant or lactating and nonpregnant or nonlactating animals for each of the studies, and the means ± SD were 38.34 ± 0.47, 39.25 ± 0.38, 39.37 ± 0.28, and 39.67 ± 0.26°C for the 33-d, 55-d, and 138-d pregnancy studies, and the 10-d lactation study, respectively. During the 33-d pregnancy study, the nonpregnant LPS-challenged sheep had a greater (P < 0.01) temperature response than the pregnant LPS-challenged animals. Significant differences were not observed in any of the other pregnancy studies (P = 0.5); however, the temperature response was marginally greater (P = 0.06) in the LPS-challenged nonlactating sheep compared with lactating LPS-challenged ewes.
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Figure 2. Change in body temperature at 4 h in response to challenge with Escherichia coli serotype O111:B4 lipopolysaccharide (LPS; 400 ng/kg of BW) in pregnant (d 33, 55, and 138), lactating (d 10), and nonpregnant nonlactating sheep. Control pregnant and lactating sheep were administered saline. A indicates differences (P < 0.05) between pregnant or lactating LPS-challenged ewes and the saline controls, whereas B indicates a difference (P < 0.05) between pregnant or lactating LPS-challenged ewes and nonpregnant LPS-challenged ewes. All values are least-squares means ± SE.
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As with the temperature data, all LPS-challenged sheep displayed an increase (P < 0.01) in cortisol concentration compared with the saline control animals (Figure 3). Basal cortisol concentrations were not significantly different between pregnant or lactating ewes and those that were nonpregnant or nonlactating for each of the studies (d 33, P = 0.23; d 55, P = 0.34; d 138, P = 0.07; d 10, P = 0.96). The means ± SD were 2.24 ± 1.88, 3.07 ± 2.11, 2.72 ± 2.18, and 2.38 ± 0.94 µg/dL for the 33-, 55-, and 138-d pregnancy studies, and the 10-d lactation study, respectively. During the 138-d pregnancy study, the pregnant ewes had a greater (P < 0.01) cortisol response to LPS than the nonpregnant sheep. Differences were not observed in any of the other pregnancy or lactation studies.
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Figure 3. Change in serum cortisol at 4 h in response to challenge with Escherichia coli serotype O111:B4 lipopolysaccharide (LPS; 400 ng/kg of BW) in pregnant (d 33, 55, and 138), lactating (d 10), and nonpregnant and nonlactating sheep. Control pregnant and lactating sheep were administered saline. A indicates differences (P < 0.05) between pregnant or lactating LPS-challenged ewes and the saline controls, whereas B indicates a difference (P < 0.05) between pregnant or lactating LPS-challenged ewes and nonpregnant LPS-challenged ewes. All values are least-squares means ± SE.
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Serum IL-6 concentrations were increased (P < 0.01) in the nonpregnant LPS-challenged sheep during the pregnancy and lactation studies. At 138 d of pregnancy and 10 d into lactation, increases (P < 0.01) in serum IL-6 concentration were also observed in the LPS-challenged pregnant and lactating ewes (Figure 4). In the 33- and 55-d pregnancy studies, the pregnant ewes did not respond to the LPS challenge with an increase in serum IL-6 concentration (P = 0.4 and 0.3, respectively). During the 138-d pregnancy study; however, IL-6 concentrations were increased (P < 0.01) in the pregnant ewes, and they were greater (P < 0.01) than the LPS challenged nonpregnant sheep. In the 10-d lactation study, the lactating ewes also responded to the LPS challenge with an increase (P < 0.01) in serum IL-6 concentration, comparable with concentrations measured in the nonlactating animals.
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Figure 4. Change in serum IL-6 at 4 h in response to challenge with Escherichia coli serotype O111:B4 lipopolysaccharide (LPS; 400 ng/kg of BW) in pregnant (d 33, 55, and 138), lactating (d 10), and nonpregnant and nonlactating sheep. Control pregnant and lactating sheep were administered saline. A indicates differences (P < 0.05) between pregnant or lactating LPS-challenged ewes and the saline controls, whereas B indicates a difference (P < 0.05) between pregnant or lactating LPS-challenged ewes and nonpregnant LPS-challenged ewes. All values are natural log [titer x 100,000] of the least-squares means ± SE.
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DISCUSSION
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The objective of this study was to examine HPAA responsiveness in sheep after a systemic challenge with E. coli LPS during various stages of pregnancy and early lactation. In addition to this, IL-6, an activator of the HPAA, and the temperature response were also investigated. Contrary to earlier studies that have reported suppression of the HPAA response during pregnancy, we observed that pregnant sheep respond to systemic LPS challenge with greater concentrations of serum cortisol than the nonpregnant animals and are thus hyperresponsive to this stressor during late pregnancy. Additionally, we observed attenuation of the temperature response during early pregnancy and lactation, whereas serum IL-6 concentrations appeared to be unchanged during the LPS challenge around early and mid pregnancy. A similar study, performed using pregnant rats challenged with a psychological stressor, displayed decreases in the cortisol response after d 15 of pregnancy compared with nonpregnant animals (Neumann, 2001). From this we conclude that the majority of HPAA changes occur during late pregnancy. The elevated serum cortisol concentrations at 138 d compared with earlier periods of pregnancy may be the result of the fetus contributing to this hyperresponsiveness. In support of this hypothesis, Challis et al. (1996) and Whittle et al. (2001) have demonstrated that the fetal HPAA is not responsive until around d 60 of gestation. Furthermore, a study using pregnant ewes challenged with 2 µg/kg of BW LPS i.v. indicated an increase in fetal plasma cortisol concentrations 2 h after maternal challenge (Grigsby et al., 2003). Additionally, in the ovine species, sustained activation of the fetal HPAA leads to an increased production of fetal cortisol during the last days of pregnancy; this is thought to contribute to the initiation of parturition (Challis et al., 2001; Whittle et al., 2001). In contrast, if the fetus was responding to the LPS by increasing fetal cortisol, one may have expected the lamb to be born prematurely. However, this was not the case in the current study. Lastly, a study performed by McClure et al. (2005) showed that fetal IL-6 and TNF- concentrations and temperature did not change in response to maternal LPS challenge (300 ng/kg of BW i.v.) at 130 d of gestation; the authors concluded that the fetus is protected from the maternal response to LPS challenge (McClure et al., 2005). Clearly, more research is needed to clarify the contribution of the fetus to the maternal cortisol response to LPS challenge.
In contrast to the pregnant sheep, we observed no change in the cortisol response to LPS challenge during lactation. This is in contrast to several rodent lactation studies that have reported attenuated response to LPS with forced swimming and physical restraint (da Costa et al., 1996; Shanks et al., 1999; Neumann, 2001). These contrasting results may be attributed to species-specific differences in the HPAA response to stress. Cattle and sheep, for example, show differential cortisol responses to seasonal environmental changes, such as heat and exercise, between lactating and nonlactating animals (Garcia-Belenguer et al., 1996; Hammond et al., 1998; Ashutosh et al., 2001). Sheep are also more sensitive to LPS than rats and may therefore display a different cortisol response (Redl et al., 1993). Breed differences within a species have also been reported. Four distinct breeds of chickens, for example, displayed different behavioral responses, BW gain, organ development, and core temperatures in response to an i.v. injection of 5.0 µg of LPS/kg of BW (Cheng et al., 2004).
In this study, we also noted an attenuation of the temperature response only during early pregnancy and early lactation. Similar results have been reported using rats challenged with 160 µg of LPS/kg of BW administered i.p. (Fofie and Rewell, 2003). Those authors suggested that the temperature hyporesponsiveness during pregnancy could be due to increased circulating IL-1 receptor antagonist concentrations that are present during this time, causing a decrease in the production of prostaglandin E2. However, this was not measured directly in the study, and thus more mechanistic evaluations need to be performed.
The temperature response to an inflammatory stressor challenge during mid and late pregnancy has given contradictory results in the literature. Our results support the findings by Heap et al. (1981), who determined that there was no attenuation of the temperature response after Clun Forest ewes were challenged with 30 µg of Salmonella abortus equi LPS i.v. (Heap et al., 1981). Similarly, comparable temperature responses between pregnant and nonpregnant white rabbits were also reported after challenge with 2 µg of LPS/kg of BW i.v. (Blatteis et al., 1986). Consistent with our results, earlier studies using lactating rats that received 25 µg of LPS/kg of BW, and lactating guinea pigs that received 4 µg of LPS/kg of BW i.m. demonstrated that the temperature response to LPS during lactation is attenuated (Zeisberger et al., 1981; Martin et al., 1995). One possible explanation for this attenuation is a reduction in cyclooxygenase-2 expression during this period, which may cause a decrease in prostaglandin E2 production (Mouihate et al., 2002). This, however, was not measured directly in the study, and thus more mechanistic studies need to be performed.
In this study, serum IL-6 production was determined to be nonresponsive in pregnant ewes after challenge with LPS during early and mid pregnancy compared with pregnant control animals. This is in contrast to a study performed using mice, which determined that there were significant differences in IL-6 concentrations between pregnant control and pregnant challenged mice but not between nonpregnant and pregnant animals during early and mid gestation receiving 50 µg of LPS/kg of BW i.p. (Vizi et al., 2001). To date, we know of no other ovine studies that have determined serum IL-6 concentrations during early or mid pregnancy in response to an i.v. bolus dose of LPS.
In contrast, our study showed that during late pregnancy serum IL-6 concentrations are increased over that of the pregnant control and the nonpregnant challenged animals. This indicates that the mechanism(s) causing nonresponsive IL-6 concentrations after LPS challenge during early and mid pregnancy was removed. These results are consistent with a study performed with third trimester mice receiving 50 µg of LPS/kg of BW i.p. (Vizi et al., 2001). In contrast to our results, a recent study that utilized sheep challenged i.v. with LPS (300 µg/kg of BW) did not indicate any significant differences in serum IL-6 concentration between nonpregnant and pregnant ewes during late pregnancy (McClure et al., 2005). These contrasting results are likely due to differences in the sampling times between the 2 studies. Serum samples were collected in our study 138 d into pregnancy, whereas the earlier study collected samples between 124 to 126 d of pregnancy. Additionally, a different E. coli serotype was used in that study (McClure et al., 2005), and the adult nonpregnant sheep had undergone an ovariectomy approximately 1 wk before LPS challenge.
In contrast to late pregnancy, the LPS challenge raised serum IL-6 concentrations equally in lactating and non-lactating sheep. This conflicts with results from a study using rats which showed that IL-6 was down-regulated in lactating animals in response to foot-shock stress (Shanks et al., 1997). On the other hand, serum IL-6 concentrations in lactating cows with acute mastitis were increased compared with healthy lactating cows (Hagiwara et al., 2001). Unfortunately, no comparison was made with nonlactating cattle in that study. Increased IL-6 secretion in vitro has been reported, however, after lactating bovine mammary epithelial cells were stimulated with LPS (Okada et al., 1999). To date, we know of no studies investigating the effect of an LPS challenge on IL-6 concentrations in early lactating sheep.
Concentrations of IL6 were measured in this study to determine whether or not there was a correlation between LPS-induced IL-6 concentrations and temperature and cortisol concentrations during pregnancy and early lactation. At 138 d of pregnancy, the increase in serum IL-6 was coincident with a similar increase of serum cortisol indicating that IL-6 may have contributed to the increase in cortisol secretion. This correlation was not observed during lactation, perhaps due to the presence of other lactogenic hormones such as prolactin, which is known to inhibit cortisol secretion (Torner and Neumann, 2002).
In summary, we have shown that sheep are affected differently during pregnancy and lactation to moderate doses of the inflammatory stressor LPS. The temperature response in ewes to E. coli LPS is attenuated during early pregnancy and early lactation in comparison with nonpregnant animals. Increased serum cortisol concentrations demonstrate responiveness of the HPAA to LPS during late pregnancy. Increased serum IL-6 concentrations at this time may have contributed to this hyperresponsiveness. During early and mid pregnancy, however, the serum IL-6 response appeared to be nonresponsive.
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Footnotes
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1 This work was supported by the Natural Sciences and Engineering Research Council Discovery Grant and Ontario Ministry of Agriculture and Food Grant awarded to N. A. Karrow. We thank Margaret Quinton for her statistical input, Jeremy Mount, Heather Drake, Carl McNicoll, and the staff at Ponsonby Research Station for their continued assistance with the animals. 
2 Corresponding author: nkarrow{at}uoguelph.ca
Received for publication October 31, 2005.
Accepted for publication February 21, 2006.
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Abstract
INTRODUCTION
