J. Anim. Sci. 2003. 81:1274-1280
© 2003 American Society of Animal Science
Central and peripheral concentrations of tumor necrosis factor-
in Chinese Meishan pigs stimulated with lipopolysaccharide1, ,2
R. Sakumoto*,3 ,
E. Kasuya*,
T. Komatsu
and
T. Akita
* Department of Physiology and Genetic Regulation, National Institute of Agrobiological Sciences, Ibaraki 305-8602, Japan, and
and
National Institute of Livestock and Grassland Sciences Ibaraki 305-0901, Japan
Correspondence:
(phone: 81-29-838-8644; fax: 81-29-838-8610; E-mail:
sakumoto{at}affrc.go.jp).
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Abstract
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The objective of this study was to investigate the presence of tumor necrosis factor-
(TNF-) in the central nervous system and the effects of lipopolysaccharide on central and peripheral concentrations of TNF-, behavioral conditions (standing or lying), elimination scores (defecation or urination), rectal temperature, and food intake (as-fed basis) in Chinese Meishan pigs. Intravenous injections of lipopolysaccharide resulted in increased (P < 0.05) plasma concentrations of TNF- and cortisol. Although urination was not affected by the administration of lipopolysaccharide, defecation was stimulated (P < 0.05). Lipopolysaccharide increased (P < 0.05) rectal temperature and standing rate, and inhibited (P < 0.05) food intake in pigs. To determine whether TNF- is present in the porcine central nervous system as well as in peripheral blood, TNF- and its specific transcripts in brain tissues (hypothalamus, amygdala, or hippocampus) and the pituitary were determined. The abundance of TNF- messenger RNA and immunoreactive TNF- were observed in all tissues, and the concentrations of TNF- were increased (P < 0.05) by the intramuscular injection of lipopolysaccharide. These results suggest that TNF- is present in the central nervous system, and plays some roles in its biological regulation in Chinese Meishan pigs.
Key Words: Brain • Lipopolysaccharides • Meishan • Pigs • Pituitary • Tumor Necrosis Factor
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Introduction
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Tumor necrosis factor- (TNF-) is a nonglycosylated protein with a molecular weight of 17 kDa; it was first described as a tumoricidal factor produced by activated macrophages (Carswell et al., 1975). In humans or rodents, it has been demonstrated that TNF- increases with the presence of several central nervous system (CNS) disorders, including multiple sclerosis (Sharief et al., 1993), cerebral malaria (Madana et al., 1997), and cerebral ischemia (Wang et al., 1994). In addition, immunoreactive TNF- has been determined in activated microglial cells, astrocytes, and periventricular areas (Lieberman et al., 1989; Gong et al., 1998). Binding sites for TNF- have been demonstrated in the cortex, basal ganglia, and thalamus (Kinouchi et al., 1991). These findings strongly suggest that TNF- affects the CNS and contributes to the behavioral and neuroendocrine changes that characterize sickness in humans and rodents. Recent studies suggest that proinflammatory cytokines, including TNF-, affect the hypothalamic-pituitary-adrenal axis and stress-induced sickness behavior in pigs (Abraham et al., 1998; Johnson, 1998; Balaji et al., 2002). However, the physiological significance and production of TNF- in the CNS in pigs are not well established.
The Meishan pig is a Chinese breed known for reproductive traits, such as increased litter size and precocious puberty, but also for slow growth and obesity (Désautés et al., 1999). An understanding of the regulatory mechanisms that lead to a high prolificacy in pigs would be important scientifically for improving the reproductive efficiency of other pig breeds. Therefore, the present study was conducted to determine whether TNF- messenger RNA is expressed and TNF- is produced in the brain and the pituitary in Meishan pigs. The effects of lipopolysaccharide (LPS) on peripheral TNF- and cortisol concentrations, rectal temperature, food intake, and behavioral conditions were also studied to determine how the Meishan pigs respond to LPS.
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Materials and Methods
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Animals
Twenty-nine prepubertal Chinese Meishan pigs were used in this study. All female pigs were supplied at a weight between 18 and 25 kg (7 to 10 wk old). All experiments employed in this study followed the recommendations within the Guide for the Care and Use of Agricultural Animals in Agricultural Research of the National Institute of Agrobiological Sciences (Tsukuba, Japan).
Experimental Design
Experiment 1.
Sixteen prepubertal Chinese Meishan pigs were weaned at 6 wk of age and housed in individual metabolism cages (0.8 x 1.3 m) in an environmentally controlled room maintained at 22°C and 60% humidity. Lights were on between 0600 and 1800. Each cage was equipped with automatic food and water dispensers to allow for ad libitum access to food and water. After an acclimation period of 7 d, each pig was surgically fitted with a jugular vein catheter (14-gauge Argyle CV Catheter Kit; Nippon Sherwood, Tokyo, Japan) under sterile conditions. Food and water were withheld overnight before surgery. Each pig was premedicated with xylazine (0.3 mg/kg of BW; Bayer AG, Leverkusen, Germany) and midazolam (0.1 mg/kg of BW; Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan). General anesthesia was induced by inhalation of halothane (1.5 to 2.5%; Takeda Chemical Industries, Ltd., Osaka, Japan) and oxygen. To avoid the pigs biting the catheter and to allow the experimenter to take blood easily without disturbing the animals, the free end of the catheter was externalized at the dorsal neck. Venous catheters were flushed daily with sterile heparinized physiological saline and were used for the administration of intravenous treatment with LPS (from E. coli Serotype 055:B5, #L-2880; Sigma Chemical Co., St. Louis, MO) and for the collection of blood samples. After recovery for 7 d from surgery, the following experiments were conducted. The pigs were tested over a 4-h period (from 0830 to 1230). The endotoxin challenge was performed by an injection of 0, 0.5, 5, or 30 µg of LPS/kg of BW (n = 4/dose) in 2 mL of sterile PBS into the vena cava via an indwelling cannula at 0930.
Behavioral conditions were monitored throughout the entire experimental period, and frequency of defecation and urination were determined. In order to evaluate the behavioral standing or lying rates, the total experimental period (4 h) was divided into 5-min periods. If the animals were standing for more than half of the 5-min period, it was regarded as "standing." Behavioral scores were evaluated as a percentage of total time. The motivation for food increased by removing the food 18 h before administering treatments. Food was returned for a 60-min test period (from 0930 to 1030), and food intake (as-fed basis) was recorded. Rectal temperature was measured with a thermo recorder (CTM-303; Terumo Inc., Tokyo, Japan). The catheter with thermo probe (2.5 mm diameter) was inserted in the rectum and was fitted to the tail with adhesive tape at 0800 (30 min before testing). This process was conducted daily during the acclimatization. Rectal temperature was monitored during a 4-h period and recorded at 5-min intervals. Blood samples were collected at 15-min intervals during a 4-h period on each test day. Blood samples were immediately centrifuged, and the resulting plasma was aliquoted into approximately 500-µL volumes and stored at -80°C until analyzed.
Experiment 2.
Three prepubertal Meishan pigs (18 to 22 kg) were used for the analysis of TNF- messenger RNA abundance. Each pig was slaughtered by electrical shock, as conducted in local abattoirs. After rapidly opening the cranial vault, the hypothalamus, amygdala, hippocampus, and pituitary were collected. The tissues were frozen rapidly on dry ice and then stored at -80°C until processed for study of gene transcription of TNF-.
Experiment 3.
Ten prepubertal Meishan pigs (18 to 25 kg) were used. Sterile physiological saline (2 mL; n = 5) or LPS (25 µg/kg of BW in 2 mL of saline; n = 5) was administered intramuscularly 1 h before euthanasia to each pig. After rapidly opening the cranial vault, the hypothalamus, amygdala, hippocampus, and pituitary were collected. Each tissue was homogenized in an ice bath with a polytron homogenizer (CH-6010; Kinematica GmBH, Switzerland). Three 20-s bursts at maximal speed with 30-s intervals of cooling between each burst were applied. The homogenate was subsequently centrifuged at 2,000 x g for 30 min at 4°C. The supernatant was used directly for ELISA.
Reverse Transcription-Polymerase Chain Reaction (RT-PCR)
Total RNA isolation and subsequent RT-PCR steps were carried out as previously described (Sakumoto et al., 2000b). Briefly, total RNA was isolated by the single-step method using TRIzol reagent (Gibco BRL, Rockville, MD) and quantified spectroscopically at 260 nm. Two micrograms of total RNA was used to generate single-strand complementary DNA (cDNA) in a 20 µL-reaction mixture using a Moloney-Murine leukemia virus reverse transcriptase (Gibco BRL). Conditions for enzymatic amplification were optimized for the PCR as follows: the PCR contained 21 µL of H2O, 50 µM of each primer (2 µL), and 25 µL of Taq PCR Master Mix (Taq PCR Master Mix kit; Qiagen K.K., Tokyo, Japan) to 2 µL of cDNA (final volume 50 µL). Samples for TNF- were amplified for 35 cycles (one single denaturation step at 95°C for 15 min, followed by 1 min at 94°C, 1 min at 60°C, and then one additional elongation step at 72°C for 1 min). As a negative control, water was used instead of RNA for the RT-PCR to exclude any contamination from buffers and tubes.
The primers encoding the porcine sequences were designed from data from the database of the European Molecular Biology Laboratory or were used as described elsewhere and commercially synthesized (Hokkaido System Science Co., Ltd., Hokkaido, Japan). The primers were chosen with an online software package (www-genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi). Two introns were included between the forward and reverse primers in order to distinguish specific PCR products from the amplification of genomic DNA. The primers were as follows: forward 5'-ATCCGAGACGTGGAGCTG-3', reverse 5 ' - A C T C T G C C A T T G G A G C T G T C - 3 ' (297 bp).
Aliquots of the PCR reaction products (10 µL) were added to 1 µL of bromphenol blue glycerin and fractionated by electrophoresis through a 2.5% agarose gel (Nacalai Tesque, Kyoto, Japan) containing ethidium bromide in a constant 100-V field. To determine the length of the products, a marker (No. 9; Nippon Gene Co., Ltd., Tokyo, Japan) was used. The ethidium bromide-stained gels were evaluated with a UV transilluminator.
Hormone Determination
Plasma and tissue TNF- levels were directly determined using commercially available ELISA kits for swine TNF- (KSC3012; BioSourse Int., Inc., Camarillo, CA). The standard curve ranged from 15.6 to 1,000 pg/mL, and the effective dose for 50% inhibition (ED50) of the assay was 220 pg/mL. The intra- and interassay coefficients of variation averaged 4.8 and 7.9%, respectively. The assay was found to have no cross-reactivity with porcine interleukins 1ß, 8, and 10, mouse TNF-, or rat TNF-. Cortisol concentrations were determined with an EIA modified from a method developed for progesterone determination (Prakash et al., 1987; Sakumoto et al., 2000a) using peroxidase-labeled cortisol (FKA403, 1:40,000 final dilution; Cosmo Bio Co., Ltd., Tokyo, Japan) and anticortisol serum (FKA404E, 1:70,000 final dilution; Cosmo Bio Co.). Cross-reactivities of the anticortisol serum, validated by comparing the inhibition of binding of peroxidase-labeled cortisol, were 100% for cortisol, 11.5% for 11-deoxycortisol, 4% for cortisone, 2% for corticosterone, 0.2% for 17-hydroxy-11-deoxy-corticosterone, 0.04% for 17-hydroxy-progesterone, 0.035% for progesterone, 0.02% for testosterone, 0.006% for androstenedione, and <0.01% for estradiol. The standard curve ranged from 0.31 to 320 ng/mL, and the ED50 of the assay was 9.1 ng/mL. The intra- and interassay coefficients of variation averaged 9.8 and 13.8%, respectively.
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Statistical Analysis
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Experimental data of the behavioral conditions, food intake, rectal temperature, and the concentrations of TNF- and cortisol are shown as the mean ± SEM. The data were analyzed by one-way ANOVA with the StatView 5 (SAS Institute Inc., Cary, NC, USA) software package. When the ANOVA showed a significant effect for the phase, phases were compared by the Fisher’s protected least-significant difference as a multiple comparison test. A probability value less than 0.05 denoted the presence of a statistically significant difference.
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Results
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Posture, Elimination Scores, and Food Intake
Figure 1
shows the effect of LPS on posture and the elimination score in the pigs. The standing rate increased and the lying rate decreased (P < 0.05) by treatment with LPS at all doses. Although the number of urinations was not affected by treatment with LPS, the number of defecations increased (P < 0.05). Treatment with LPS made the pigs decrease (P < 0.05) their food intake in a dose-dependent manner (Figure 2).
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Figure 1. Effects of lipopolysaccharide (LPS) on a) posture and b) elimination scores in Meishan pigs. All values are expressed as the mean ± SEM (four pigs per treatment). *Significant differences compared to the control, as determined by an analysis of variance followed by Fisher’s protected least-significant difference as a multiple comparison test (P < 0.05).
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Figure 2. Effects of lipopolysaccharide (LPS) on food intake (as-fed basis) in Meishan pigs. All values are expressed as the mean ± SEM (four pigs per treatment). Different superscript letters indicate significant differences (P < 0.05), as determined by an analysis of variance followed by Fisher’s protected least significant difference as a multiple comparison test.
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Rectal Temperature, Concentrations of TNF- and Cortisol After LPS Treatment
The results of the effect of LPS on rectal temperature are shown in Figure 3a. As expected, rectal temperature increased (P < 0.05) with the stimulation of LPS. Intravenous injection of LPS caused increases in plasma TNF- and cortisol concentrations (P < 0.05). Lipopolysaccharide (30 µg/kg) stimulated (P < 0.05) the TNF- concentration during the 45- to 135-min period after administration (Figure 3b). In contrast, the same dose of LPS stimulated (P < 0.05) cortisol concentrations during the 45- to 180-min period after administration (Figure 3c).
TNF- in the Tissues of Brain and Pituitary
Specific transcripts for TNF- were detected in the tissues of the hypothalamus, amygdala, hippocampus and pituitary (Figure 4). The PCR product showed 100% homology to the known porcine gene after sequencing. The TNF- concentrations in the brain and the pituitary tissues are given in Figure 5. Immunoreactive TNF- was present in all the tissues examined. Lipopolysaccharide stimulated (P < 0.05) TNF- concentrations in all of the tissues. The basal and LPS-induced TNF- concentrations in the pituitary were lower (P < 0.05) than those of the other tissues.
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Discussion
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The preceding results clearly demonstrate that the TNF- gene and immunoreactive TNF- are present in porcine brain and pituitary tissues, and that the TNF- concentrations are increased by treatment with LPS. These findings suggest that TNF-, locally produced in the brain and the pituitary, plays a role in regulating CNS function in Chinese Meishan pigs.
It is generally accepted that LPS induces sickness behaviors, including respiratory failure, anorexia, diarrhea, somnolence and hypersomnia (Olson et al., 1985; Johnson and von Borell, 1994; Warren et al., 1997). As expected in this study, food intake was reduced by the treatment with LPS in a dose-dependent manner. Previous reports have demonstrated that TNF- stimulates leptin production from adipose tissues (Finck et al., 1998). Leptin has been known as a potent inhibitor of food intake in pigs (Barb et al., 1998). Although the central regulatory mechanisms of anorexia remain to be clarified, we assume that LPS may directly or indirectly affect food intake in pigs concomitant with TNF- or leptin secretion. On the other hand, intravenous treatment with LPS resulted in an increased behavioral standing rate and a decrease in lying rate in pigs. Because LPS is known to stimulate sickness behaviors including somnolence, it was unexpected in the present study that LPS would decrease the lying rate in pigs. An appropriate explanation for this phenomenon was not apparent. One possible explanation might be due to the different experimental conditions, including the dose of LPS and the stimulation time compared to previous studies.
Lipopolysaccharide stimulated both plasma cortisol and TNF- concentrations in the Meishan pigs in this study. The stimulatory effect of LPS on TNF- production was acute and transient compared with the effect on cortisol production. In contrast, cortisol production by stimulation of LPS was gradually increased, and these effects were continued until the end of the experimental period. Because cytokines, including TNF-, have been recognized as stimulants of cortisol production, LPS-induced TNF- could contribute to the stimulation of cortisol production in Meishan pigs. On the other hand, glucocorticoids, including cortisol, are known to inhibit cytokine secretion by inflammatory cells (Sternberg, 2001). In the present study, LPS-stimulated production of TNF- was reduced sooner than that of cortisol. Sustained high concentrations of cortisol might inhibit TNF- secretion in the pigs.
Messenger RNA for TNF- and immunoreactive TNF- were observed in the hypothalamus, amygdala, hippocampus, and pituitary of Meishan pigs. Furthermore, the contents of TNF- were increased by the stimulation of LPS. Because tissue homogenates that were obtained from whole blocks of brain tissues and the pituitary were used in the present study, it was not possible to say which neuron or cell types produced TNF- in the porcine CNS. It has been shown that TNF- is produced mainly by macrophages/monocytes, microglia, and astroglia in brain explants (Lieberman et al., 1989; Chung and Benveniste, 1990; Gong et al., 1998). Moreover, endothelial cells have been shown to produce TNF- (Hehnke et al., 1995). Hence, it was assumed that these cells in the CNS produce TNF- in the Meishan pigs. On the other hand, binding sites for TNF- have been demonstrated in the cortex, basal ganglia, and thalamus of the rat brain (Kinouchi et al., 1991). Kull et al. (1985) showed the presence of high-affinity binding sites for TNF- on aortic endothelial cells, suggesting the presence of TNF- receptors in cerebral endothelial cells. It has been demonstrated that TNF- contributes to an alteration of blood–brain barrier permeability in the brains of rodents (Sharief and Thompson, 1992). In addition, TNF- is reported to induce fever through direct action on hypothalamic neurons (Dinarello CA, 1988). Intracerebroventricular injections of TNF- in pigs resulted in induced anorexia, hypersomnia, and an abrupt increase in plasma cortisol concentration (Warren et al., 1997). It has been demonstrated that ACTH secretion by anterior pituitary cells was influenced by TNF- (Abraham et al., 1998). Thus, based on these findings and the present study, TNF- may act in porcine CNS in an autocrine and/or paracrine fashion.
In the present study, the TNF- concentration in peripheral blood could not be determined before the administration of LPS. In contrast, the tissue contents of TNF- in the brain and the pituitary were observed without the stimulation of LPS. Although a direct comparison of the TNF- concentration between plasma and tissue extracts is not possible, it may be speculated that TNF- plays a role not only in inflammatory responses, but also in other normal situations in pigs. Further studies are needed to clarify these points. Studies on the diurnal variation of TNF- and the localization of functional TNF- receptors in the porcine CNS must be determined.
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Implications
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The present study demonstrated the presence of tumor necrosis factor- in the porcine brain and the pituitary, as well as in peripheral blood. Also, it was shown that concentrations of tumor necrosis factor- were increased by the stimulation of lipopolysaccharide. Although the cellular localization of tumor necrosis factor- and its receptors in the porcine brain remains to be determined, these findings suggest that tumor necrosis factor- plays some roles in the central nervous system, as well as in peripheral organs. Furthermore, this study confirmed that lipopolysaccharide stimulated standing rate, defecation number, rectal temperature, blood cortisol concentrations, and decreased food intake in Chinese Meishan pigs.
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Footnotes
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1 This research was supported by a Grant-in-Aid for Scientific Research (No. 14760183) of the Japan Society for the Promotion of Science (JSPS). 
2 The authors thank Y. Watanabe (National Institute of Agrobiological Sciences) for her skilled technical assistance.
Received for publication September 9, 2002.
Accepted for publication January 15, 2003.
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Abstract
Introduction
