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Participation of Pterins in the Control of Lymphocyte Stimulation and Lymphoblast Proliferation1

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Participation of Pterins in the Control of Lymphocyte Stimulation and Lymphoblast Proliferation1 [CANCER RESEARCH 43, 5356-5359, November 1983] Participation of Pterins in the Control of Lymphocyte Stimulation and Lymphoblast Proliferation1 Irmgard Ziegler,2 Ulrike Hamm, and J. Berndt Gesellschaft fur Strahlen-und Umweltforschung, Institut fur Toxikologie und Biochemie, Abteilung Zellchemie, Arcisstrasse 16, 0-8000 München2[l. Z., U. H.], and D- 8042 Neuherberg [J. B.], West Germany ABSTRACT Early investigations into pterins during regeneration experi ments (11), during growth of solid tumors (12), and during egg Biopterin accumulation had been demonstrated as the result development (8) had shown an inhibitory action of isoxantho of normal and, especially, of malignant hemopoietic cell prolifer pterin on cell proliferation. Conversely, the levels of blood biop ation (Ziegler, I. ef al. Blut, 44: 231-240, and 261-270, 1982). terin and of a pteridine-binding variant of c^-acid glycoprotein Among 13 major intermediates of pterin metabolism and two had indicated a stimulatory effect of some pterin intermediates lumazines, xanthopterin (but not dihydroxanthopterin) was found to inhibit cell proliferation (half-maximum inhibition at 1.8 x 10~5 on hemopoietic cell proliferation (4). These data suggested that pterins not only are products of M) during concanavalin A-induced lymphocyte activation in pre- cell proliferation but may have a regulatory function. For verifi stimulated lymphocytes and in a lymphoid cell line grown in cation, the effect of the major intermediates of pterin metabolism continuous culture (LS-2). LS-2 cells exposed to maximum inhib on Con A3-induced lymphocyte activation and on the proliferation itor concentrations largely maintained the initial thymidine incor of a LCL was examined. poration rate for about 40 hr but failed to enter logarithmic growth. Isoxanthopterin inhibition was found only in serum-free medium, since it is trapped by the a-acid glycoprotein present in MATERIALS AND METHODS the serum. The reduced biopterin derivatives, sepiapterin, dihy- Chemicals. All components of the tissue culture medium, PCS, and drobiopterin, and tetrahydrobiopterin, are costimulators during Con A were from Seromed (Berlin, West Germany). The microtest plates concanavalin A-induced lymphocyte activation. Their costimula- were obtained from Nunc (Wiesbaden, West Germany), and the dThd tory effect follows an optimum curve and peaks at 1.5 to 3 x was from Amersham Buchler (Braunschweig, West Germany). 7,8-Di- 10~5 M. It is highest at the suboptimal and supraoptimal concan hydrobiopterin, 7,8-Dihydroneopterin, sepiapterin, tetrahydrobiopterin, avalin A concentration. The o-erythro isomer dihydroneopterin neopterin, and biopterin were commercially obtained from B. Schircks was inactive. The results indicate that the anabolic-reduced (Wetzikon, Switzerland). Leucopterin, xanthopterin, pterin, and lumazine were from Sigma Chemical Co. (St. Louis, Mo.). 7,8-Dihydroxantho- biopterin derivatives are not simply lymphocytic products, but, in pterin, 6-hydroxylumazine, 6-hydroxymethylpterin, and sepiapterin were combination with the catabolites xanthopterin and isoxantho- a gift from W. Pfleiderer (Konstanz, West Germany). 6-Methylpterin and pterin, they also participate in the regulation of lymphocyte 6-hydroxymethylpterin were obtained from J. Bieri (Zürich,Switzerland). activation. Hence, they fulfill the criteria for lymphokines. Source of the Cells and Culture Conditions. The lymphoid cell line LS-2, established in 1974 by J. Lange (Stuttgart, West Germany) from a INTRODUCTION patient with acute lymphocytic leukemia, was obtained from the Institut fürKlinische Hämatologie der Gesellschaft fürStrahlen-und Umweltfor As is the case in all other organisms, mammalian pterin syn schung, München, West Germany. Its characteristics are described thesis starts with GTP (6). The first intermediate is o-erythro- elsewhere (14). dihydroneopterin triphosphate. It is metabolized via sepiapterin Mouse spleen lymphocytes were obtained from male inbred mice (strain 101; Neuherberg, West Germany), aged 7 to 9 weeks. After to dihydrobiopterin and tetrahydrobiopterin. The current view on having been cut into pieces, the spleens were teased aseptically through the biosynthetic pathway of tetrahydrobiopterin in humans has wire gauze and processed further as described previously (13). The cells been summarized previously (2). were suspended in Roswell Park Memorial Institute Medium 1640, which The 3 biopterin derivatives, as determined by crithidia assay, was supplemented with L-glutamine (2 rriM), NaHCO3 (0.2%), 2-mercap- were found to be accumulated in the blood cells during hemo toethanol (0.1 mw), penicillin (100 lU/ml), and streptomycin (100 ^g/ml); poietic cell proliferation in beagles (23) and, especially, to be a if not indicated otherwise, 5% inactivated PCS was added. marker of increased proliferation in leukemias; high concentra Assay Conditions, Application of Pteridines, and Determination of tions of biopterin were found in blasts (22). Recently, neopterin Cell Growth. The assays were set up in round-bottomed wells of 96- was identified among the fluorescent compounds found in the fold sterile microtest plates. The final volume in each well was always medium of alloantigen-induced lymphocytes (5). 0.2 ml, which was composed of 0.1 ml medium (plus the compounds to be tested) and 0.1 ml cell suspension. The cultures were started at a Xanthopterin, dihydroxanthopterin, isoxanthopterin, and leu- density of 7.5 x 106 cells/ml. The prestimulation of lymphocytes was run copterin are considered to be the main products among the for 24 hr with 2.5 ?g Con A per ml in 1.5-ml batches; after centrifugation, pterin catabolites (16). Deamination gives rise to the lumazine they were exposed to the experimental conditions further for a 48-hr series (17). period. The application of pteridines was started from stock solutions of 5.6 x 10~3 M. Reridines with lower solubility at pH 7 (e.g., xanthopterin and 1The investigation was supported by Grant Zi 153/3 from the Deutsche For schungsgemeinschaft. 2To whom requests for reprints should be addressed. 3 The abbreviations used are: Con A, concanavalin A; LCL, lymphoid cell line Received March 8. 1983; accepted July 14. 1983. grown in continuous culture; PCS, fetal calf serum; dThd, [6-3H]thymidine. 5356 CANCER RESEARCH VOL. 43 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1983 American Association for Cancer Research. Regulatory Function of Pterins in Lymphocyte Stimulation isoxanthopterin) had to be dispersed by Bonification (1 min; Branson Chart 1 and Table 1 survey the structures of the pteridines Sonifier B). The stock solutions were kept frozen; the reduced com used and their action on the Con A-induced lymphocyte stimu pounds were freshly prepared. The stock solutions were diluted 1:10 lation. Most of the pteridines had no effect. The reduced biopterin with medium or with the medium containing the indicated concentrations derivatives promoted the Con A-induced activation, whereas the of Con A. The serial dilutions started with the addition of 0.1 ml of the 6- or 7-hydroxy-substituted pterins, xanthopterin and isoxan diluted pteridine solution plus 0.1 ml of either medium or Con A-oontaining thopterin, were inhibitory. These costimulators and inhibitors are medium. Many of the pterins and all of the reduced ones are markedly light (UV) sensitive. Therefore, even their exposure to dim artificial light analyzed in more detail in the following sections. was minimized to sec. The Inhibitory Action of Xanthopterin and Isoxanthopterin. After 68 hr incubation (37°; 5% CO2; humidified atmosphere), 1 ¿iCi Xanthopterin, which was present from the beginning of Con A stimulation, showed a half-maximal inhibition at 1.8 x 10~5 M dThd (0.4 Ci/mmol) in 20 n\ medium was added to each well, and the incubation continued for 2 additional hr. The cells were harvested on (Chart 2A). Since isoxanthopterin was supposed to interfere with glass-fiber filters using a sample harvester (Flow, Meckenheim, West RNA and DMA synthesis (8), the action of xanthopterin on cell Germany). The uptake of dThd was measured by liquid scintillation. proliferation after previous Con A stimulation and on the growth The stimulation of the lymphocytes was determined by the increment of LCL (line LS-2) was also assayed. In these systems, the between the uptake of the unstimulated lymphocytes (1371 ±148 cpm; concentration for half-maximal inhibition was 3.1 x 10~5 M (Chart S.D.) and the stimulated ones. The data for the absolute values (Charts 2A). The action of xanthopterin on the relative dThd uptake was 3 and 4) were from 8 samples in one assay; these assays were run at the same in 5% PCS and in serum-free medium. None of the least in triplicate. The relative uptake data (Charts 2 and 5) were derived from 16 to 24 measurements. In these experiments, the controls (Con proliferating cell systems was inhibited by 7,8-dihydroxantho- A-activated lymphocytes and LCL in medium) were set to 100. The actual pterin. incorporation rates of these controls are given in the chart legends. In the routinely used 5% PCS medium, isoxanthopterin had no effect (Chart 26). Recent studies (20) had shown that isoxan thopterin, but not xanthopterin, is bound to «i-acidglycoprotein. RESULTS Since this glycoprotein, in contrast to xanthopterin, amounts to Screening of Pteridines for Their Effect on Con A-induced 0.7 to 1.0 mg/ml serum (10), the added isoxanthopterin might Lymphocyte Activation. The activation of lymphocytes was have been trapped. Therefore, the action of isoxanthopterin on assayed at Con A concentrations ranging from 0.078 to 20 u.gj the proliferation of the LS-2 cells was studied in 1% PCS and in ml. The optimum concentration was 2.5 fig/mi. An illustration of serum-free medium. As shown in Chart 28, the reduction or the Con A optimum curve is given in Reference 21, Fig. 4a. omission of PCS led to an inhibition of LS-2 proliferation by isoxanthopterin, even though this inhibition was less marked than that caused by xanthopterin.
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