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(Journal of Leukocyte Biology. 2002;72:1148-1153.)
© 2002 by Society for Leukocyte Biology

Monocyte-derived dendritic cells release neopterin

Barbara Wirleitner{ddagger}, Daniela Reider*, Susanne Ebner*, Günther Böck{dagger}, Bernhard Widner{ddagger}, Matthias Jaeger{ddagger}, Harald Schennach§, Nikolaus Romani* and Dietmar Fuchs{ddagger},||

Institutes for
{ddagger} Medical Chemistry and Biochemistry, and for
{dagger} Experimental Pathology, University of Innsbruck and
* Department of Dermatology, University of Innsbruck;
§ Central Institute for Blood Transfusion and Immunology, University Hospital, Innsbruck; and
|| Ludwig Boltzmann Institute of AIDS-Research, Innsbrugh, Austria

Correspondence: Dr. Dietmar Fuchs, Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria. E-mail: Dietmar.Fuchs{at}uibk.ac.at


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Increased neopterin concentrations in body fluids are found in diseases associated with activated, cell-mediated immunity including infections, autoimmune diseases, and certain malignancies. Monocytes/macrophages are known to secrete large amounts of neopterin upon stimulation with interferon-{gamma} (IFN-{gamma}). Ontogenetically, the major part of dendritic cells (DC) belongs to the myeloid lineage. Therefore, we investigated whether cultured monocyte-derived DC can elaborate neopterin. Cells were treated with cytokines in the presence or absence of monocyte-conditioned medium as a maturation stimulus. DC secreted an average 3.5 nmol/l neopterin. In response to IFN-{gamma}, cells significantly increased their output of neopterin. In distinction to monocytes/macrophages, neopterin production in DC was highly sensitive to IFN-{alpha} and IFN-ß. Further, lipopolysaccharides (LPS) enhanced neopterin synthesis, whereas tumor necrosis factor {alpha}, interleukin (IL)-1ß, IL-2, IL-10, and IL-18 were ineffective. Simultaneously, tryptophan degradation by induction of indoleamine (2,3)-dioxygenase (IDO) was tested in stimulated cells. Our results showed that IFN-{gamma} as well as LPS are inducers of IDO in DC.

Key Words: IFN-{gamma} • pteridines • tryptophan degradation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Increased amounts of neopterin [D-erythro-6-(1',2',3'-trihydroxypropyl)-pterin] in body fluids are associated with a variety of diseases in which activation of cellular immune mechanisms is involved, such as certain malignancies, allograft rejection, autoimmune diseases, and viral infections such as HIV [1 2 3 ]. Biochemically, neopterin originates from the cleavage of guanosine triphosphate (GTP) by GTP-cyclohydrolase I, yielding 7,8-dihydroneopterin triphosphate, the joint precursor of dihydroneopterin, neopterin, tetrahydrobiopterin, a necessary cofactor of aromatic amino acid monooxygenases, and nitric oxide synthases (NOS). Human monocytes/macrophages are unique to produce an excess of neopterin derivatives at the expense of 5,6,7,8-tetrahydrobiopterin [4 ] as a result of a comparably low activity of 6-pyrovoyltetrahydropterin synthase (PTPS), the first enzyme in the conversion of 7,8-dihydroneopterin triphosphate to tetrahydrobiopterin [5 ]. Upon activation of cellular immunity, interferon-{gamma} (IFN-{gamma}) induces GTP-cyclohydrolase I and also stimulates the enzyme indoleamine (2,3)-dioxygenase (IDO) in various cells [6 , 7 ]. The enzyme catalyzes the initial step of tryptophan catabolism within the biosynthetic pathway of nicotinamide dinucleotides, and as a first intermediate, N-formyl-kynurenine is formed. The simultaneous determination of kynurenine and tryptophan concentrations has proven to be a sensitive estimate to monitor the activation status of IDO and of cellular immunity, in vivo and in vitro [8 , 9 ].

Ontogenetically, the major part of dendritic cells (DC) belongs to the myeloid lineage. Besides their role of potent activators of quiescent T cells, DC may play a pivotal role in the induction of peripheral tolerance [10 , 11 ]. The properties of DC that determine their stimulatory, inhibitory, and regulatory roles have not been elucidated yet, and it is possible that DC express a complex repertoire of positive and negative signaling molecules including cytokines and other compounds [12 ]. Therefore, we investigated in this study, whether DC can elaborate neopterin, and we compared the results with the extent of cytokine-induced degradation of tryptophan.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Culture media
Cultivated DC were maintained in RPMI 1640 (PAA Laboratories, Linz, Austria) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 50 µg/ml gentamicin, and 2 mM L-glutamine. For differentiation of DC, supernatants of interleukin (IL)-4-producing cells (generously provided by Antonio Lazavecchia, Bellinzona, Switzerland) were used. IL-4 cells were maintained in Iscove’s modified Dulbecco’s medium (IMDM; PAA Laboratories) supplemented with 10% FBS, 50 µg/ml gentamicin, 2 mM L-glutamine, 1% natriumpyruvate, 1% nonessential amino acids, 5 µg/ml mycophenolic acid, and 100 µg/ml xanthine. For production of IL-4 medium, cells were cultured in supplemented IMDM without mycophenolic acid and xanthine for 4 days. Supernatants were harvested by centrifugation (460 g/room temperature, 8 min), sterile-filtered, and frozen at -20°C until use. As maturation stimulus, monocyte-conditioned medium (MCM) was used. To this end, isolated human peripheral blood mononuclear cells (PBMCs) were plated at a density of 5 x 107 cells/10 ml in RPMI 1640 supplemented as described above in {gamma}-globuline (Sigma Chemical Co., Vienna, Austria)-covered plates. After incubation for 1 h at 37°C, nonadherent cells were removed by gently washing culture dishes with prewarmed phosphate-buffered saline (PBS). After further incubation for 24 h, supernatant was harvested, sterile-filtered, and frozen until use.

Isolation of precursor cells
Peripheral blood from healthy donors was obtained, and PBMCs were isolated from whole blood by density centrifugation in Lymphoprep (Nycomed Pharma, Oslo, Norway). Cells were washed with cold PBS containing 1 mM EDTA, and T cells were depleted by rosetting with sheep erythrocytes. Rosetted cells were removed by density centrifugation in Lymphoprep.

Generation and stimulation of DC
Immature DC were generated as described earlier [13 , 14 ]. Briefly, isolated cells were plated in six-well plates at a density of 2 x 106 cells/well in 3 ml complete RPMI 1640 with 800 U/ml granulocyte macrophage-colony stimulating factor (GM-CSF; Leukomax, Sandoz, Basel, Switzerland) and 10% supernatant of IL-4-producing cells. Cultures were fed every other day by removing 1 ml medium and adding back 1.5 ml complete RPMI 1640 with cytokines (1600 U/ml GM-CSF and 10% IL-4 supernatant). In contrast to previous protocols, isolated monocytic cells were stimulated with GM-CSF and IL-4 for 10 days. On day 10, nonadherent cells were harvested, analyzed on a FACScan, and plated at a density of 2 x 106 cells/ml in 48-well plates in complete RPMI 1640 with 800 U/ml GM-CSF and IL-4 supernatant (10%) with or without MCM (33%) as maturation stimulus. At the same time, DC were stimulated with cytokines IFN-{gamma} (Bioferon, Laupenheim, Germany), IFN-{alpha}, IFN-ß, IL-1ß, IL-2, IL-10, IL-18, and tumor necrosis factor {alpha} (TNF-{alpha}; Strathmann Biotech, Hamburg, Germany) or lipopolysaccharides (LPS; Sigma Chemical Co.).

FACS analysis
After 10 days stimulation with IL-4 and GM-CSF and following stimulation with MCM, DC populations were analyzed by binding to fluorescence-coupled antibodies against CD3, CD14, CD72, CD83, and CD86 including isotype controls (PharMingen, Heidelberg, Germany).

Measurement of neopterin, tryptophan, and kynurenine in supernatants
After 72 h incubation of DC, supernatants were removed and centrifuged, and neopterin was determined by enzyme-linked immunosorbent assay (Brahms, Berlin, Germany). Tryptophan and kynurenine concentrations were determined by high-pressure liquid chromatography using 3-nitro-L-tyrosine as external standard [15 ]. The UV absorption of kynurenine at 360 nm wavelength and the natural fluorescence of tryptophan at 286 nm excitation and 366 nm emission wavelengths were monitored.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Phenotype of immature and mature DC
Treatment of isolated monocytic cells with IL-4 and GM-CSF for 10 days yielded cells negative for CD3, CD14, CD72, and CD83 and moderate for CD86 (Fig. 1 ). After further treatment with MCM for 3 days, a high percentage of cells positive for CD86 and CD83 was observed.



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  		Figure 1. Phenotypic analysis of DC cultures. Cells were assayed after incubation with IL-4 and GM-CSF for 10 days (a–d) an after further stimulation with MCM (A–D). a and A, Isotype-control mouse immunoglobulin G (IgG)1-PE and mouse IgG2a-fluorescein isothiocyanate (FITC); b, anti-CD14-FITC (1.19% positive); c, anti-CD83-PE (10.7% positive); d, anti-CD86-PE (18.2% positive); B, anti-CD14-FITC (2.03% positive); C, anti-CD83-PE (60.1% positive); D, anti-CD86-PE (52.4% positive).

 
Neopterin production of DC
Unstimulated DC secreted 3.5 nmol/l neopterin on average (range 2.0–12.2 nmol/l; n=28). There was no significant difference between populations treated with or without maturation stimulus (Fig. 2 ). Stimulation of DC with IFN-{gamma} led to a rise in neopterin production (~5.8-fold induction of neopterin production when stimulated with 100 U/ml IFN-{gamma} and 8.0-fold induction treated with 1000 U/ml IFN-{gamma}), whereas cells cotreated with maturation stimulus MCM were found to release less neopterin (2.5-fold induction when treated with 100 U/ml and 4.7-fold induction with 1000 U/ml IFN-{gamma}). In contrast to monocytes/macrophages [16 ], DC showed the same output of neopterin in response to low doses of IFN-{alpha} and IFN-ß compared with IFN-{gamma}. Addition of 100 U/ml IFN-{alpha} showed a 5.7-fold induction of neopterin production in cells without MCM and a 8.3-fold induction in cells cotreated with MCM. Comparable results were obtained in stimulations with 100 U/ml IFN-ß (5.3-fold induction in cells without MCM and 8.6-fold induction in the presence of MCM). IFN-{gamma}, IFN-{alpha}, and IFN-ß also augmented neopterin production in cells with maturation stimulus when used at high concentrations (1000 U/ml). TNF-{alpha} was ineffective in enhancing neopterin production in DC with or without maturation stimulus.



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  		Figure 2. Production of neopterin by immature DC with or without maturation stimulus MCM treated with IFN-{alpha}, IFN-ß, IFN-{gamma}, or TNF-{alpha} or left untreated (control). Figure shows mean ± SEM. P values according to the Mann-Whitney U test: Immature DC: IFN-{alpha} 100 U/ml = 0.002, 1000 U/ml = 0.001; IFN-ß 100 U/ml = 0.008, 1000 U/ml = 0.001; IFN-{gamma} 100 U/ml = 0.003, 1000 U/ml = 0.000; TNF-{alpha} 50 U/ml = not significant (n.s.), 500 U/ml = n.s.; DC cotreated with MCM: IFN-{alpha} 100 U/ml = 0.006, 1000 U/ml = 0.003; IFN-ß 100 U/ml = 0.006, 1000 U/ml = 0.003; IFN-{gamma} 100 U/ml = 0.006, 1000 U/ml = 0.003; TNF-{alpha} 50 U/ml = n.s., 500 U/ml = n.s.

 
We further tested the effect of bacterial LPS on neopterin elaboration in DC. The majority of LPS tested in this study led to a significant up-regulation of neopterin production in DC, whereas cotreatment with MCM slightly decreased neopterin output (Fig. 3 ). In addition, we tested various cytokines in their ability to augment neopterin production in cultured monocyte-derived DC. IL-1ß, IL-2, IL-10, and IL-18 were found to be ineffective in enhancing neopterin elaboration in DC in our experiments (Table 1 ).



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  		Figure 3. Production of neopterin by DC cultured with or without maturation stimulus MCM in response to LPS. Figure shows mean ± SEM. P values according to the Mann-Whitney U Test: Immature DC: E. coli 055:B5 = 0.287; E. coli 026:B6 = 0.054; E. coli L9641 = 0.000; Salmonella typhimurium = 0.007; Klebsiella pneumoniae = 0.028; DC cotreated with MCM: E. coli 055:B5 = 0.033; E. coli 026:B6 = 0.005; E. coli L9641 = 0.005; S. typhimurium = 0.017; K. pneumoniae = 0.006.

 

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  		Table 1. Formation of Neopterin by DC Stimulated with Different ILs

 
IDO activation in cultured DC
Simultaneously, tryptophan degradation via IDO was determined by evaluating kynurenine and tryptophan concentrations in supernatants of DC cultures. In supernatants of unstimulated, immature DC, an average of 0.52 µM kynurenine was detected after 72 h incubation (Fig. 4a ). A significant raise in IDO activation determined by kynurenine production and tryptophan degradation was observed upon stimulation of immature DC with IFN-{gamma}, 100 or 1000 U/ml, and with high dosages of IFN-ß. The most potent inducer of IDO in immature DC was LPS derived from Escherichia coli. In comparison, DC treated with MCM were found to produce a higher amount of kynurenine (mean 0.86 µM) in unstimulated control experiments (Fig. 4b) , and most possibly, as a result of the preactivation of IDO during maturation of DC, cells were less responsive to stimuli. A clear reduction of tryptophan and a simultaneous increase in kynurenine were detected in the presence of 1000 U/ml IFN-{gamma} and LPS.



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  		Figure 4. Tryptophan (lower row) and kynurenine (upper row) concentrations in culture supernatants of stimulated DC without (a) or with (b) MCM. Cells were stimulated with IFN-{alpha}, IFN-ß, or IFN-{gamma} (100–1000 U/ml), TNF-{alpha} (50–500 U/ml), or LPS (E. coli EH100; 10 µg/ml). Figure shows mean ± SEM. P values according to the Kruskal-Wallis test: (a): kynurenine = 0.033; tryptophan = 0.039; (b): kynurenine = n.s.; tryptophan = n.s.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results presented here clearly show that cultured monocyte-derived DC are a rich source of neopterin. Neopterin concentration determined in serum or urine is used as a sensitive marker for a variety of diseases including certain malignancies, allograft rejection, and autoimmune and infectious diseases [1 , 2 ]. IFN-{gamma} induces GTP-cyclohydrolase I activity, the first enzyme in the biosynthesis of neopterin, in a large variety of cells [5 ]. Among them, monocytes/macrophages were thought to be the unique source of neopterin biosynthesis in response to treatment with IFN-{gamma} [4 ]. The production of neopterin derivatives by monocytes/macrophages was found to be a result of the low activity of PTPS [17 ], and it is very likely that it is also the case for neopterin production in DC, as a result of the common precursors.

Immature DC were found to produce large amounts of neopterin in response to IFN-{gamma}. In contrast, DC coincubated with MCM and IFN-{gamma} released less neopterin, correlating with earlier data describing the down-regulation of the IFN-{gamma} receptor in mature DC [18 ]. Our data show that besides IFN-{gamma}, IFN-{alpha} and IFN-ß are also potent inducers of neopterin release in DC. An in vitro induction of neopterin release in response to IFN-{alpha} and IFN-ß has been described in monocytes/macrophages. However, neopterin production in DC seems to be much more sensitive to IFN-{alpha} and -ß compared with earlier data on monocyte-derived macrophages. Monocytes/macrophages stimulated with 100 U/ml IFN-{gamma} produced ~180% neopterin compared with immature or MCM-treated DC. In contrast, when treated with 100 U/ml IFN-ß, immature DC neopterin production was 64% compared with monocytes/macrophages incubated with the same amount of cytokine, whereas MCM-treated DC did not differ. Neopterin production induced by 100 U/ml IFN-{alpha} was 150% in immature DC and 200% in DC treated with MCM as compared with monocytes/macrophages [16 ]. The potential induction of neopterin synthesis in DC by IFN-{alpha} fits very well to the finding that in vivo injection of recombinant IFN-{alpha} is followed by a marked increase of neopterin levels in the absence of IFN-{gamma} [19 ]. Similar to monocytes/macrophages, bacterial LPS was an effective inducer of neopterin biosynthesis in DC. In comparison, stimulation of DC with 10 µg/ml LPS from E. coli caused a lower (approximately one-fifth) output of neopterin than in monocytes/macrophages [16 ]. In both cell types, LPS showed assimilable induction of neopterin elaboration than did IFN-{gamma}. Ineffective on neopterin production in DC were TNF-{alpha} and a wide range of ILs. Simultaneous with neopterin production, nitrate/nitrite concentrations in culture supernatants of DC were measured to test an activation of the inducible NO-synthase and thereby production of tetrahydrobiopterin in stimulated cells. Cultured DC without additional cytokine stimuli showed a high rate of NO production, and no further increase in nitrate/nitrite was detected after various stimulations.

Recent data suggest that neopterin derivatives exhibit distinct biochemical functions. Neopterin was found to enhance the effects of toxic reactive oxygen species originating from chloramine T and hydrogen peroxide [20 , 21 ], suggesting that neopterin derivatives are able to modulate macrophage-induced cytotoxicity by the induction of oxidative stress. In rat vascular smooth muscle cells, neopterin stimulates redox-sensitive intracellular signal transduction cascades, thereby triggering inducible NOS (iNOS) gene expression at the mRNA level with a subsequent increase in NO production [22 ]. In the same cells [23 ] and in Jurkat cells [24 ], neopterin derivatives were found to activate nuclear factor (NF)-{kappa}B. Neopterin derivatives were also shown to induce programmed cell death mediated by reactive oxygen intermediates in T-lymphoblastic cell lines and in rat alveolar cells [23 , 24 ]. In regard to these multiple biochemical functions of neopterin derivatives, it is very likely that DC might also use neopterin derivatives in the regulation of T cell response. Uniquely in humans and primates, high concentrations of neopterin are detected during cellular immune activation produced by monocytes/macrophages and most possibly, also by DC as shown in this paper. In all other organisms, activation of cellular immunity is accompanied by increased production of tetrahydrobiopterin, an essential cofactor for iNOS. NO production by iNOS seems to play a role in inflammation, e.g., by acting regulatory on NF-{kappa}B, an important modulator of inflammatory gene expression including proinflammatory cytokines and endothelial cell adhesion molecules (reviewed in ref. [25]). The production of neopterin derivatives instead of biopterin derivatives in humans raises the suggestion that neopterin derivatives substitute regulatory, immunological functions especially of the tetrahydrobiopterin-induced NO generation.

In context with the finding that DC produce neopterin derivatives upon stimulation, we additionally determined the degree of IDO-dependent tryptophan degradation, as neopterin production and IDO activation were found to closely correlate in a large variety of diseases in vivo, including systemic lupus erythematosus and HIV, but also in pregnancy [8 , 26 , 27 ]. Therefore, supernatants from stimulated DC were assayed for tryptophan and kynurenine to determine IDO activation. The cytokine IFN-{gamma} as well as LPS were found to significantly augment kynurenine production and decrease tryptophan levels in supernatants of DC. Similar to neopterin production, cells cotreated with MCM were found to be less sensitive to IDO induction by IFN-{gamma} compared with DC cultured without MCM. Our results are in good correlation with recent publications describing activation of IDO not only in monocytes but also in cultured monocyte-derived DC in response to maturation stimuli [28 , 29 ]. In contrast to macrophages, murine DC were found to constitutively express IDO, and IDO-mediated apoptosis of T cells by CD8{alpha}+ DC was demonstrated [30 ].

It is known that DC are the most potent activators of naïve T cells. Recently, the existence of inhibitory and tolerogenic DC within the bulk population of monocyte-derived DC was reported [10 , 31 ]. Myeloid DC were found to contribute to tumor-induced immune suppression in mice [32 ]. Immature myeloid DC are found in circulation of cancer patients, the number of DC positively correlating with disease stage [33 ]. These DC inhibit T cell proliferation in an antigen-nonspecific manner, through mechanisms that remain to be elucidated. Another system in which DC promote tolerance is the UV B light-treated skin Langerhans cells. These cells are capable of inactivating T cells or skewing their response to a toleroginec T helper cell type 2 profile (reviewed in ref. [34]). Postulated mechanisms are the Fas/Fas-ligand system, or the secretion of an IL-12 antagonistic protein [35 , 36 ]. Activation of IDO in macrophages and DC may contribute to unresponsiveness of T cells by depletion of tryptophan [37 , 38 ]. Indeed, in patients, a decrease of serum tryptophan and a parallel increase of kynurenine as a result of IDO activation were found in various diseases associated with T cell activation such as virus infections, autoimmune disorders, and malignant diseases. More recently, activation of IDO in monocytes/macrophages was found to interfere with the proliferative capacity of T cells in response to antigenic stimulation by withdrawing tryptophan [38]. However, the exact mechanisms of how DC execute their T cell regulatory functions still remain to be elucidated. The production of neopterin by DC might play an additional role in the down-regulation of T cell activation in vivo, as neopterin derivatives have been shown to act inhibitory on T cell proliferation [23 , 24 ]. From our results, one could hypothesize that IFN-{gamma} uses more than one pathway to down-regulate T cell immune response and that DC might use IDO-mediated tryptophan degradation and neopterin production to exert their inhibitory and regulatory properties on T cell activation.


   ACKNOWLEDGEMENTS
 
This work was supported by the Austrian Science Foundation "zur Förderung der wissenschaftlichen Forschung" (Grant P14154-MED). We thank Anni Eiter for excellent technical assistance.

Received July 4, 2002; revised August 22, 2002; accepted September 12, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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