HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Melchior, D. Articles by Le Floc’h, N. Search for Related Content PubMed PubMed Citation Articles by Melchior, D. Articles by Le Floc’h, N.

Chronic lung inflammation affects plasma amino acid concentrations in pigs¹

Institut National de la Recherche Agronomique, Unité Mixte de Recherche sur le Veau et le Porc, 35590 Saint Gilles, France

Abstract

Metabolic changes associated with inflammatory processes and immune response can modify protein and AA requirements. Improved knowledge of these processes will provide opportunities for nutritional intervention to sustain growth and animal defense at the same time. The objective of the study was to identify AA whose metabolism is affected by chronic lung inflammation. Six pairs of littermate piglets were selected at 28 d of age on the basis of their BW. After catheterization of the jugular vein, one littermate received complete Freund’s adjuvant (CFA) intravenously, whereas its littermate was injected with a sterile saline solution (CON). Piglets within a litter were pair-fed in order to avoid confounding effects of feed intake and inflammation on plasma AA concentrations. Blood samples were taken after an overnight fast and 2 h after the morning meal for 9 d. Rectal temperature, food consumption, weight gain, plasma haptoglobin, and AA concentrations were measured. The CFA injection decreased food intake, and increased body temperature and plasma haptoglobin concentration. Plasma tryptophan, glutamine, proline, glycine, tyrosine, ornithine, total AA concentrations, and the ratio of tryptophan to large neutral AA were less in CFA than in CON (P < 0.05), independent of time and meal. In contrast, plasma histidine concentration was higher (P < 0.05) in CFA than in CON pigs. Plasma serine, arginine, alanine, asparagine, and total AA concentrations were lower in CFA than in CON pigs only in the fed state (P < 0.05). Among essential AA, only plasma tryptophan concentration was lower (P < 0.01) in CFA than in CON pigs in both fasted and fed state. These results show that chronic lung inflammation affects individual AA differently and suggest that the utilization of some AA increased during chronic lung inflammation in pigs. Activation of tryptophan catabolism enzyme indoleamine 2,3-dioxygenase seems a relevant hypothesis to explain the increased tryptophan utilization, although its incorporation in acute-phase proteins and the existence of other catabolic pathways cannot be excluded.

Key Words: Amino Acid • Haptoglobin • Inflammation • Pigs • Tryptophan

Introduction

Permanent exposure to infectious or noninfectious antigens prevents farm animals from expressing their growth potential even when the disease is subclinical. The detrimental effects of immune stress on food intake, growth, and muscle gain often result in considerable economic loss for the livestock producers. The adaptive response to antigen stimulation occurs through a combination of actions of cytokines, released by activated immune cells and hormones. Proinflammatory cytokines (interleukin-1 [IL-1], IL-6, tumor necrosis factor) induce great metabolic changes; they provoke hyperthermia, anorexia, and muscle protein breakdown, and increase protein synthesis by the liver (Klasing and Johnstone, 1991; Grimble et al., 1992). As a consequence, nutrients are diverted from growth processes toward tissues and cells involved in inflammatory and immune responses (Klasing, 1988). Amino acids provided by food and accelerated muscle protein catabolism are used as substrates for gluconeogenesis and immune cell proliferation. They can serve as substrates for inflammatory protein and immunoglobulin synthesis as well (Grimble et al., 1992). Moreover, some of these could play specific roles closely related to immune response and body defense. Little is known about AA requirements altered by inflammation and immune response in pigs. A better knowledge of these requirements will help in proposing new nutritional strategies to preserve both growth and body defenses. To this end, the objective of this study was to identify AA whose metabolism is affected by chronic lung inflammation induced by intravenous complete Freund’s adjuvant (CFA) injection in piglets. Plasma AA concentrations were used as indicators of AA metabolism disturbance. To avoid confounding the effect of decreased feed intake and inflammation on plasma AA concentrations, healthy control animals were pair-fed the intake of animals treated with CFA.

Materials and Methods

Animals Care and Feeding
All procedures were performed according to current French legislation on animal experimentation (authorization to experiment on animal No. 7719 delivered by the French Ministry of Agriculture and Fisheries). Seven litters of crossbred Piétrain x (French Landrace x Large-White) piglets were weaned at 28 d of age. Seven days after weaning, six pairs of littermates were selected on the basis of their sex and BW (11 x 0.5 kg BW). These 12 pigs were housed in individual cages in an environmentally controlled building with alternate lighting, and temperature was maintained at 26°C. An indwelling silicone catheter (0.76 x 1.65 mm, Ercelab Vermed, Neuilly-en-Thalle, France; catalog ref. 48175) was implanted through a collateral vein in the right external jugular vein. The catheter tube was placed under the skin, externalized at the dorsum of the neck, and put in a bag sutured to the skin. Surgery was performed under general anesthesia induced with ketamine (Imalgene 100, Merial, France) and maintained thereafter with 2 to 5% halothane (Belamont, Boulogne Billancourt, France) in oxygen. The catheters were flushed daily with 10 mL of sterile saline solution containing 2.5 mL of heparin (5,000 U/mL).

Ten days after surgery and following an overnight fast, one piglet per pair was slowly injected i.v. with 3 mL of CFA (Sigma Aldrich, Saint Quentin Fallavier, France; catalog No. F-5881) in 10 mL of physiological sterile saline solution. Complete Freund’s adjuvant is a mineral oil containing killed Mycobacterium tuberculosis cells. The six other piglets were injected with the same volume of sterile saline and constituted a control group (CON).

Pigs were fed with a standard Phase II postweaning diet (Table 1) twice a day. The AA:lysine ratios met the requirement for growing piglets as determined by Chung and Baker, (1992). The amount of allocated food was limited to 40 g/kg of BW (as-fed basis). Because inflammation can induce anorexia, CON pigs were pair-fed the intake of the CFA pigs. Food intake of CFA piglets was measured after 1 h, and the same quantity of food was then offered to the saline-injected littermate. All pigs had free access to water.

Plasma haptoglobin was analyzed according to a spectrophotometric method (Elson, 1974). A solution containing excess cyanmethemoglobin was added to the plasma sample. Plasma haptoglobin binds to cyanmethemoglobin according to a fixed stochiometric ratio. Following addition of a formate sodium buffer (150 mL formic acid, 1 M, and 50 mL NaOH, 1 M, pH 3.7), free cyanmethemoglobin will be denatured, whereas the haptoglobin–cyanmethemoglobin complex will be protected. The UV absorbance was measured at 405 nm for the test (cyanmethemoglobin–haptoglobin complex) and the reference (denatured cyanmethemoglobin) and corrected with measurement of the absorbance at 380 nm. Plasma haptoglobin was expressed as cyanmethemoglobin-binding capacity calculated as follows: (test 405 - reference 405) - (test 380 - reference 380) and expressed in absorbance units (U).

Plasma AA concentrations were determined after plasma deproteinization in a sulfosalicylic acid solution (60g/L) combined with an internal standard (norvaline). Chromatographic separation of AA was performed on a Biotronik LC 5001 analyzer (Biotronik, Pusheim Bahnhof, Germany) according to the method of Moore and Stein. (1954). A second run was performed to analyze free tryptophan.

Calculations and Statistical Analysis
Because of the loss of catheter patency for one piglet, statistical analyses were performed on five pairs of pigs. Data were analyzed with the MIXED procedures of SAS (SAS Inst., Inc., Cary, NC). The model included challenge (CFA injected vs. CON), pair, time (d), meal effect (fasted vs. fed) and their interactions. The interaction effects challenge x pair, meal x challenge x pair, and time x challenge x pair were introduced in the model as random effects. Because fed and fasted haptoglobin concentrations were not significantly different, all data were pooled for the analysis of the challenge effect.

Results

Animal Observations
Following CFA injection, pigs became lethargic and rapidly showed increased respiratory rhythm. There was no mortality in the CFA group. After 2 d, CFA piglets seemed to recover, but some of them coughed. At slaughter, macroscopic granulous pulmonary lesions were observed in all CFA pigs.

Food Intake and Growth Performance
Before injection, pigs ate all the offered food. Food consumption per day was affected (P < 0.01) by CFA injection (Figure 1). One day after the challenge, food consumption per day was reduced to approximately half the allocated amount. There was no food refusal from 2 to 8 d after CFA injection. However, at the end of the second week of experiment, food refusals were recorded again for the CFA piglets. On d 10 after CFA injection, the average amount of consumed food per day by piglet was lower (P < 0.01) than the allocated amount. The ADG was not significantly affected by the challenge. The ADG were 338 ± 12 g/d for the CFA group and 350 ± 20 g/d for the CON group.

View larger version (12K): [in this window] [in a new window]   Figure 1. Average daily food consumption (as-fed basis) by piglets injected i.v. with 3 mL of complete Freund’s adjuvant (CFA) compared with the allocated amount. Symbols denote significant differences between allocated and consumed food (**P < 0.01; n = 5).

View larger version (13K): [in this window] [in a new window]   Figure 2. Rectal temperature in pigs injected intravenously with saline (CON) or 3 mL of complete Freund’s adjuvant (CFA). Data are least squares means ± SEM; n = 5 per treatment mean. "Basal" represents data from blood samples 3 d before i.v. CFA injection.

View larger version (13K): [in this window] [in a new window]   Figure 3. Plasma haptoglobin concentrations in pigs injected intravenously with saline (CON) or 3 mL of complete Freund’s adjuvant (CFA). The absorbance indicates cyanmethemoglobin-binding capacity to haptoglobin. Data are least squares means ± SEM; n = five per treatment mean. "Basal" represents data from blood samples 3 d before i.v. CFA injection.

Plasma tryptophan and glycine concentrations were significantly lower in CFA than in CON pigs both in the fed (P < 0.05) and fasted state (P < 0.01). In addition, the difference was more pronounced in the fed state. For these two AA, challenge x meal x time interaction effects were also significant (P < 0.05 and P < 0.01, respectively). For glycine in the fed state, the CON - CFA difference increased 1 and 2 d after CFA injection, disappeared on d 3 and 4, and then reappeared on d 7 to 9. In the fasted state, the CON minus CFA difference followed the same pattern according to time but was less pronounced than in the fed state. For Trp, in the fed state, the CON minus CFA difference increased following CFA injection until d 2, decreased, without disappearing on d 3 and 4, and increased again continuously until the end of the experiment (Figure 4). In the fasted state, the CON minus CFA difference increased following CFA injection during the whole experimental period (Figure 5).

View larger version (13K): [in this window] [in a new window]   Figure 4. Fed plasma tryptophan concentrations in pigs injected intravenously with saline (CON) or 3 mL of complete Freund’s adjuvant (CFA). Data are least squares means ± SEM; n = 5 per treatment mean. "Basal" represents data from blood samples 3 d before i.v. CFA injection.

View larger version (14K): [in this window] [in a new window]   Figure 5. Fasting plasma tryptophan concentrations in pigs injected intravenously with saline (CON) or 3 mL of complete Freund’s adjuvant (CFA). Data are least squares means ± SEM; n = 5 per treatment mean. "Basal" represents data from blood samples 3 d before i.v. CFA injection.

The present study was designed to identify AA whose metabolism was affected during chronic inflammation. We selected a model that mimics a chronic disease with an inflammatory response similar to conditions that could be observed in conventional pig farms. The model had to generate long-term perturbations of protein and AA metabolism without inducing severe clinical and metabolic disorders or mortality. Such perturbations can be induced by infectious challenges using living bacteria or viruses (Asai et al., 1999; Magnusson et al., 1999; Balaji et al., 2000). One of the most common noninfectious immune challenges used in animal studies is bacterial lipopolysaccharide (LPS) administration. This model has been used extensively to study the body’s response to immune system stimulation in poultry (Webel et al., 1998) and pigs (Webel et al., 1997; Wright et al., 2000). However, the endotoxin model presents two disadvantages: first, the lethal dose of endotoxins depends largely on individual animal sensitivity; second, when administration is not lethal, recovery of the animals occurs typically in less than 48 h, whereas repeated administration leads to endotoxin tolerance. Consequently, the LPS model is appropriate to study acute rather than chronic immune responses. We selected a noninfectious model of chronic lung inflammation involving i.v. injection of CFA (Edwards and Slauson, 1983). Pigs displayed a three phases response to CFA injection. An acute response within 2 d after the challenge injection, followed by a transient and partial recovery, where rectal temperature and food intake returned to control level, and finally, a late response suggesting onset of chronic inflammation. The chronicity was confirmed by the haptoglobin response, the existence of lung lesions, and other criteria, such as reduced food consumption and increased rectal temperatures. Pigs had persistent signs of increased respiratory rhythm but no evident signs of pain. The latter observation may be explained by the fact that lung tissue possesses few nociceptors.

Haptoglobin Is a Good Indicator of Chronic Lung Inflammation in Piglets
This study showed increased levels of plasma haptoglobin in pigs experimentally challenged with CFA. Previous studies also have reported marked responses in plasma haptoglobin concentrations to various types of immunological stress (Lampreave et al., 1994; Eckersall et al., 1996; Heegaard et al., 1998). Corticosteroids, IL-1, and IL-6 are involved in acute-phase protein synthesis in the liver (Marinkovic et al, 1989); therefore, the level of plasma haptoglobin concentration reflected the immune system activation mediated by these molecules. Haptoglobin plays numerous roles during immunological stress including antioxidant, antiinflammatory, antibacterial activities, and modulation of immune response (Wassell, 2000). Plasma haptoglobin variation over time is of interest because of its high level in the blood 10 d after CFA injection. Higher serum haptoglobin concentrations were observed in pigs infected with the porcine reproductive and respiratory syndrome virus than in healthy controls 21 d after inoculation (Asai et al., 1999). Because plasma concentration remained high for several days after challenge induction, contrary to the typical transient response of cytokines, haptoglobin seems to be a good indicator of chronic inflammation and infection in pigs.

Plasma Amino Acid Concentrations Are Affected by Chronic Lung Inflammation
In this experiment, plasma AA concentrations were chosen as indicators of changes in AA metabolism. Protein synthesis and AA catabolism tend to decrease free plasma AA concentrations, whereas plasma free AA may be increased by protein degradation, dietary intake, and de novo synthesis of nonessential AA. Modifications of two opposite fluxes may be without consequence on the plasma concentrations. Thus, in our experimental conditions, we cannot exclude that the metabolism of some AA was modified without effect on plasma concentrations. Nevertheless, in the present study, plasma concentrations of histidine were higher in pigs with chronic lung inflammation than in pair-fed healthy controls. No difference in plasma histidine concentration was observed between infected and healthy pigs (Yoo et al., 1997). However, a relative accumulation of this AA in the plasma has been described in children suffering from falciparum malaria (Enwonwu et al., 1999). The increase in plasma histidine concentration could be the result of an increased muscle catabolism, currently observed during inflammation (Wannemacher, 1977), as well as an inhibition of its catabolizing enzyme (Enwonwu et al., 1999).

The lower total AA concentrations in CFA than in CON pigs is consistent with observations made in pigs with enterotoxigenic Escherichia coli peritonitis (Yoo et al., 1997), in AIDS patients (Laurichesse et al., 1998), and in patients with obstructive pulmonary disease (Pouw et al., 1998). The decrease in AA concentrations following inflammatory diseases could reflect a decrease in food consumption and in absorption. In the present experiment, pair feeding of healthy control piglets enabled the assessment of the specific effect of inflammation on plasma AA concentration. During immune challenge, a decrease in plasma AA concentrations can also be explained by an increase in AA utilization to 1) provide energy and protein nutrients for cell proliferation; 2) serve as substrate for molecules involved in inflammation and body defense; or 3) enter specific metabolic pathways related to body defenses. In CFA pigs, more AA are decreased in the fed than in the fasted state, suggesting that when AA are supplied, they are more rapidly metabolized in CFA than in CON pigs. During immune and inflammatory responses, metabolic changes are associated with an increase in basal metabolic rate, resulting in increased energy utilization and a switch from fatty acids to glucose as a preferred source by many tissues (Klasing and Johnstone, 1991). Therefore, lower plasma concentrations of gluconeogenic AA, such as glutamine, serine, or glycine in CFA pigs could be the result of increased catabolism to support gluconeogenesis and provide energy for immune cell proliferation. Besides, according to Grimble (1992), the production of many substances that require sulfur-containing AA, such as glycine and serine, is increased during inflammation. Glycine is one of the three AA of glutathione, an important tripeptide involved in antioxidant defenses. Therefore, the decline in plasma glycine concentration with lung inflammation may reflect increased tissue uptake to support glutathione synthesis. Nevertheless, glycine is the most abundant AA in the plasma pool of pigs (Yoo et al., 1997) and is generally not limiting. In septic rats, it has been demonstrated that cysteine was the first-limiting AA for glutathione synthesis (Malmezat, 2000).

Inflammation and body defenses are characterized by an increase in hepatic synthesis of acute-phase protein (APP) and their appearance in the plasma. The APP are known to play crucial roles in the defense against pathogens and the modulation of immune response. Reeds et al. (1994) reported that human APP are relatively rich in aromatic AA (phenylalanine, tryptophan, and tyrosine) compared with muscle protein. According to their calculations, and assuming muscle protein is the major source for these AA, particularly in situations of severe decrease in food consumption, 1.5 to 2 g of protein should be degraded to release the amounts of AA necessary for the synthesis of 1 g of APP (Reeds et al., 1994). The decrease in plasma tyrosine and tryptophan in pigs affected by lung inflammation in this study may be due to incorporation into APP. This is further supported by results obtained in humans showing negative correlations between plasma tryptophan concentrations and the plasma concentrations of APP, transferrin, haptoglobin (Maes et al., 1993) and fibrinogen (Preston et al., 1998). In contrast, incorporation of phenylalanine in APP would be compensated by fluxes that bring this AA to the plasma pool. What emerges from these results and other studies on the alterations of AA metabolism during inflammatory and immune responses is that not all individual essential AA change in the same manner. The change in individual plasma AA concentration depends on the balance between its specific utilization to support inflammatory and immune responses and its release to the plasma pool from protein catabolism and food intake. In this respect, the particular response of Trp to inflammation in our study deserves a specific discussion.

Increased Tryptophan Catabolism During Inflammation in Pigs
Tryptophan is the only essential AA for which plasma concentrations are significantly decreased by lung inflammation. Tryptophan concentration was affected by lung inflammation in both fed and fasted states and remained significantly lower in CFA compared with CON pigs in the fasted state throughout the experimental period. These observations support the hypothesis that tryptophan could become a limiting essential AA in pigs suffering from chronic lung inflammation. The decrease in plasma tryptophan concentrations has been observed in various situations of immune stress in mice (Saito et al., 1992), pigs (Lindberg and Clowes, 1981; Yoo et al., 1997), and humans (Brown et al., 1991; Pfefferkorn, 1984). Whether this decrease is due to synthesis of APP as mentioned above remains speculative and requires experimental evidence in pigs. Over the last 10 yr, tryptophan metabolism and its relation to inflammation and immune response has been extensively studied in rats and human patients (Brown et al., 1991). Indoleamine 2,3 dioxygenase, a rate-limiting enzyme for the catabolism of tryptophan to kynurenine, was found to be induced by interferon- (MacKenzie and Hadding, 1998; Pfefferkorn, 1984) and other cytokines (Liebau et al., 2002). This induction usually results in decreased plasma tryptophan and increased plasma kynurenine concentrations (Meyer et al., 1995; Widner et al., 2000). We measured kynurenine concentrations in the remaining plasma of three pairs of piglets and found significantly greater plasma kynurenine concentrations in CFA than in CON pigs at the end of the experiment (P < 0.05, data not shown). This result supports the hypothesis that tryptophan was catabolized to kynurenine during chronic lung inflammation in pigs. Local tryptophan depletion under indoleamine 2,3 dioxygenase activation has been proposed as an inducible host defense mechanism (Pfefferkorn, 1984; MacKenzie and Hadding, 1998), a cell proliferation modulator (Mellor and Munn, 1999), and as a free-radical protector mechanism (Christen et al., 1990). Also, tryptophan (Watanabe et al., 2002) and several of its derivatives, not only from the kynurenine pathway but also from serotonin and melatonin biosynthesis pathways, may function as free-radical scavengers and antioxidants (Goda et al., 1999). Therefore, tryptophan utilization may be increased to satisfy inflammation and general body defenses requirements.

We hypothesized that an increased utilization of tryptophan during inflammation and immune response reduces its availability for growth and other physiological functions involving this AA. In pigs, both the decrease in plasma tryptophan concentration and the ratio of plasma tryptophan:LNAA could alter appetite (Henry et al., 1992). In the present study, the tryptophan:LNAA ratio was decreased by the challenge. The role of tryptophan in appetite regulation has been explained by several hypotheses, including the decrease in serotonin synthesis for which the precursor is tryptophan and the induction of tissue resistance to insulin (Sève, 1999). Based on this knowledge, the decrease in plasma tryptophan concentration may eventually alter appetite in pigs experiencing chronic immune system stimulation. Also, the proinflammatory cytokine IL-1 has been well documented in the literature as an appetite regulator (Rothwell and Luheshi, 2000).

The data generated in this study directly show that the plasma AA profile is modified by chronic lung inflammation in pigs. Pigs challenged with CFA showed a marked decrease in tryptophan plasma concentration, suggesting an increase in tryptophan utilization. Catabolism resulting from indoleamine 2,3 dioxygenase activation as well as tryptophan incorporation into APP appear relevant hypothesis to explain tryptophan utilization. Studies using labeled tryptophan should provide answers on quantitative importance of these pathways.

Implications

An area of interest in animal nutrition is the amino acids requirement induced by inflammation and immune response. Improved knowledge of these processes will provide new opportunities for nutrition intervention to better meet nutrient requirements for immune response and growth. This experiment indicated that the utilization of some amino acids, such as tryptophan, is increased during chronic lung inflammation in pigs and suggests an active role for this essential amino acid in inflammatory and immune responses. From a practical point of view, this is important because tryptophan is a limiting amino acid for growth in corn-based diets for pigs.

Footnotes

¹ We thank F. Legouëvec, Y. Lebreton, N. Mézière, and Y. Colléaux for their technical assistance.

² Supported by the Institut National de la Recherche Agronomique, France and Ajinomoto Eurolysine, France.

³ Correspondence—e-mail: lefloch{at}st-gilles.rennes.inra.fr.

Received for publication May 12, 2003. Accepted for publication December 18, 2003.

Literature Cited

Asai, T., M. Mori, M. Okada, K. Uruno, S. Yazawa, and I. Shibata. 1999. Elevated serum haptoglobin in pigs infected with porcine reproductive and respiratory syndrome virus. Vet. Immunol. Immunopathol. 70:143–148.[Medline]

Balaji, R., K. J. Wright, C. M. Hill, S. S. Dritz, E. L. Knoppel, and J. E. Minton. 2000. Acute phase responses of pigs challenged orally with Salmonella typhimurium. J. Anim. Sci. 78:1885–1891.[Abstract/Free Full Text]

Brown, R. R., Y. Ozaki, S. P. Datta, E. C. Borden, P. M. Sondel, and D. G. Malone. 1991. Implications of interferon-induced tryptophan catabolism in auto-immune diseases and AIDS. Adv. Exp. Med. Biol. 294:425–435.[Medline]

Christen, S., E. Peterhans, and R. Stocker. 1990. Antioxidant activities of some tryptophan metabolites: Possible implication for inflammatory diseases. Proc. Natl. Acad. Sci. USA 87:2506–2510.[Abstract/Free Full Text]

Chung, T. K., and D. H. Baker. 1992. Utilization of methionine isomers and analogs by the pig. Can. J. Anim. Sci. 72:185–188.

Eckersall, P. D., P. K. Saini, and C. McComb. 1996. The acute phase response of acid soluble glycoprotein, ₁-acid glycoprotein, ceruloplasmin, haptoglobin and C-reactive protein, in the pig. Vet. Immunol. Immunopathol. 51:377–385.[Medline]

Edwards, J. F., and D. O. Slauson. 1983. Complete Freund’s adjuvant-induced pneumonia in swine : A model of interstitial lung disease. J. Comp. Pathol. 93:353–361.[Medline]

Elson, E. C. 1974. Quantitative determination of serum haptoglobin. A simple and rapid method. Am. J. Clin. Path. 62:655–663.[Medline]

Enwonwu, C. O., B. M. Afolabi, L. A. Salako, E. O. Idigbe, H. Al-Hassan, and R. A. Rabiu. 1999. Hyperphenyalaninaemia in children with falciparum malaria. Q. J. Med. 92:495–503.

Goda, K., Y. Hamane, R. Kishimoto, and Y. Ogishi. Radical scavenging properties of tryptophan metabolites. Estimation of their radical reactivity. Adv. Exp. Med. Biol. 467.397–402.

Grimble, R. F., A. A. Jackson, C. Persaud, M. J. Wride, F. Delers, and R. Engler. 1992. Cysteine and glycine supplementation modulate the metabolic response to tumor necrosis factor- in rats fed a low protein diet. J. Nutr. 122:2066–2073.

Heegaard, P. M. H., J. Klausen, J. P. Nielsen, N. Gonzales-Ramon, M. Pineiro, F. Lampreave, and M. A. Alava. 1998. The porcine acute phase response to infection with Actinobacillus pleuropneumoniae. Haptoglobin, C-reactive protein, major acute phase protein and serum amyloid A protein are sensitive indicators of infection. Comp. Biochem. Physiol. B 119:365–373.[Medline]

Henry, Y., Y. Colléaux, P. Ganier, A. Saligaut, and P. Jégo. 1992. Interactive effects of dietary levels of tryptophan and protein on voluntary feed intake and growth performance in pigs, in relation to plasma free amino acids and hypothalamic serotonin. J. Anim. Sci. 70:1873–1887.[Abstract]

Klasing, K. C. 1988. Nutritional aspects of leukocytic cytokines. J. Nutr. 118:1436–1446.

Klasing, K. C., and B. J. Johnstone. 1991. Monokines in growth and development. Poult. Sci. 70:1781–1789.[Medline]

Lampreave, F., N. Gonzales-Ramon, S. Martinez-Ayensa, M. A. Hernandez, H. C. Lorenzo, A. Garcia-Gil, and A. Pineiro. 1994. Characterization of the acute phase serum protein response in pigs. Electrophoresis 15:672–676.[Medline]

Laurichesse, H., I. Tauveron, F. Gourdon, L. Cormerais, C. Champredon, S. Charrier, C. Rochon, S. Lamain, G. Bayle, H. Laveran, P. Thieblot, J. Beytout, and J. Grizard. 1998. Threonine and methionine are limiting amino acids for protein synthesis in patients with AIDS. J. Nutr. 128:1342–1348.[Abstract/Free Full Text]

Liebau, C., A. W. A. Baltzer, S. Schmidt, C. Roesel, C. Karreman, J. Bernd Prisack, H. Bojar, and H. Merk. 2002. Interleukine-12 and Interleukine-18 induce indoleamine 2,3-dioxygenase (IDO) activity in human osteosarcoma cell lines independently from interferon-. Anticancer Res. 22:931–936.[Medline]

Lindberg, B. O., and G. H. Clowes, Jr. 1981. The effects of hyperalimentation and infused leucine on the amino acid metabolism in sepsis: an experimental study in vivo. Surgery 90:278–290.[Medline]

MacKenzie, C. R., and U. Hadding. 1998. Interferon-gamma_induced activation 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. J. Infect. Dis. 178:875–878.[Medline]

Maes, M., H. Y. Meltzer, S. Scharpé, E. Bosmans, E. Suy, I. De Meester, J. Calabrese, and P. Cosyns. 1993. Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Research 49:151–165.[Medline]

Magnusson, U., B. Wilkie, K. Artursson, and B. Mallard. 1999. Interferon-alpha and haptoglobin in pigs selectively bred for high and low immune response and infected with Mycoplasma Hyorhinis. Vet. Immunol. Immunopathol. 68:131–137.[Medline]

Malmezat, T., D. Breuillé, C. Pouyet, C. Buffière, P. Denis, P. Patureau Mirand, and C. Obled. 2000. Methionine transsulfuration is increased during sepsis in rats. Am. J. Physiol. Endocrinol. Metab. 279:1391–1397.

Marinkovic, S., G. P. Jahreis, G. G. Wong, H. Bauman. 1989. IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo. J. Immunol. 142: 808–812.[Abstract]

Mellor, A. L., and D. A. Munn. 1999. Tryptophan catabolism and T-cell tolerance: Immunosupression by starvation? Immunol. Today 20:469–473.[Medline]

Meyer, K. C., R. A. Arend, M. V. Kayaloglu, N. S. Rosenthal, G. I. Byrne, and R. R. Brown. 1995. Tryptophan metabolism in chronic inflammatory lung disease. J. Lab. Clin. Med. 126:530–540.[Medline]

Moore, S., and W. H. Stein. 1954. Procedures for the chromatographic determination of amino acids on four per cent cross-linked sulfonated polystyrene resins. J. Biol. Chem. 211:893–906.[Free Full Text]

Pfefferkorn, E. R. 1984. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc. Natl. Acad. Sci. USA 81:908–912.[Abstract/Free Full Text]

Pouw, E. M., A. M. W. Schols, N. E. P. Deutz, and E. F. M. Wouters. 1998. Plasma and muscle amino acid levels in relation to resting energy expenditure and inflammation in stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care. Med. 158:797–801.[Abstract/Free Full Text]

Preston, T., C. Slater, D. C. McMillan, J. S. Falconer, A. Shenkin, and K. C. H. Fearon. 1998. Fibrinogen synthesis is elevated in fasting cancer patients with an acute phase response. J. Nutr. 128:1355–1360.[Abstract/Free Full Text]

Reeds, P. J., C. R. Fjeld, and F. Jahoor. 1994. Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states? J. Nutr. 124:906–910.

Rothwell, N. J., and G. N. Luheshi. 2000. Interleukin I in the brain: Biology, pathology and therapeutic target. Trends Neurosci 23:618–625.[Medline]

Saito, K., S. P. Markey, and M. P. Heyes. 1992. Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neurosciences 51:25–39.[Medline]

Sève, B. Physiological roles of tryptophan in pig nutrition. Adv. Exp. Med. Biol. 467:729–741. 1999.[Medline]

Wannemacher, R. W. 1977. Key role of various individual amino acids in host response to infection. Am. J. Clin. Nutr. 30:1269–1280.[Free Full Text]

Wassell, J. 2000. Haptoglobin: Function and polymorphism. Clin. Lab. 46:547–552.[Medline]

Watanabe, S., S. Togashi, N. Takahashi, and T. Fukui. 2002. L-Tryptophan as an antioxidant in human placenta extract. J. Nutr. Sci. Vitaminol. 48:36–39.

Webel, D. M., B. N. Finck, D. H. Baker, and R. W. Johnson. 1997. Time course of increased plasma cytokines, cortisol, and urea nitrogen in pigs following intraperitoneal injection of lipopolysaccharide. J. Anim. Sci. 75:1514–1520.[Abstract/Free Full Text]

Webel, D. M., R. W. Johnson, and D. H. Baker. 1998. Lipopolysaccharide-induced reductions in food intake do not decrease the efficiency of lysine and threonine utilization for protein accretion in chickens. J. Nutr. 128:1760–1766.[Abstract/Free Full Text]

Widner, B., M. Ledochowski, and D. Fuchs. 2000. Interferon-gamma-induced tryptophan degradation: Neuropsychiatric and immunological consequences. Curr. Drugs Metab. 1:193–204.

Wright, K. J., R. Balaji, C. M. Hill, S. S. Dritz, E. L. Knoppel, and J. E. Minton. 2000. Integrated adrenal, somatotropic, and immune responses of growing pigs to treatement with lipopolysaccharide. J. Anim. Sci. 78:1892–1899.[Abstract/Free Full Text]

Yoo, S. S., C. J. Field, and M. I. McBurney. 1997. Glutamine supplementation maintains intramuscular glutamine concentrations and normalizes lymphocyte function in infected early weaned pigs. J. Nutr. 127:2253–2259.[Abstract/Free Full Text]

This article has been cited by other articles:

				D. A. Scott, S. M. Hickerson, T. J. Vickers, and S. M. Beverley The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major J. Biol. Chem., January 4, 2008; 283(1): 155 - 165. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Melchior, D. Articles by Le Floc’h, N. Search for Related Content PubMed PubMed Citation Articles by Melchior, D. Articles by Le Floc’h, N.