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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 4 1177-1180
Copyright © 1997 by The Endocrine Society

Experimental Studies

Decreased Interleukin-2 Production from Cultured Peripheral Blood Mononuclear Cells in Human Acute Starvation1

Lars Sävendahl2 and Louis E. Underwood

Department of Pediatrics, Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Dr. L. Sävendahl, Department of Pediatrics, Umea University, S-901 85 Umea, Sweden. E-mail: lars.savendahl{at}histocel.umu.se


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Depressed cell-mediated immunity and decreased insulin-like growth factor I (IGF-I) are observed in malnourished humans. To study the interaction among nutrition, IGF-I, and cytokines, healthy volunteers (six men and four women, aged 21–38 yr, weighing 93–124% of ideal body weight) were subjected to a 7-day fast (mineral water only). Fasting steadily decreased serum IGF-I from 247 ± 29 (prefast) to 87 ± 10 ng/mL (postfast; P < 0.0001), total T cells (CD3+) from 1499 ± 68 to 1308 ± 70 x 109 (P < 0.0001), and T helper cells (CD4+) from 997 ± 62 to 856 ± 55 x 109 (P < 0.001). Peripheral blood mononuclear cells were isolated and cultured in serum-free RPMI 1640 for 24 h. Fasting attenuated peripheral blood mononuclear cell production of interleukin-2 in response to various concentrations of phytohemagglutinin P [PHA-P; 347 ± 48 (prefast) vs. 135 ± 52 pg/mL (postfast) when challenged with 3 µg/mL PHA-P; P < 0.005 when comparing dose-response curves (1–100 µg/mL PHA-P)]. Although the approximately 3-fold suppression of interleukin-2 and IGF-I in subjects fasted for 1 week is not likely to affect immune function significantly, our results with this short term model of nutrient restriction provide insight into possible mechanisms for immune suppression in chronic starvation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PROTEIN-ENERGY deficiency is the most common cause of acquired immunodeficiency in humans, primarily affecting cellular immune function (1, 2). Acute starvation in normal humans causes rapid loss of body weight and proteins and can be used as a model for studying the effects of protein-energy malnutrition on the immune system (3).

Insulin-like growth factor I (IGF-I), which is known to exert a wide array of biological effects on a variety of cell types, is suppressed by acute or chronic protein-calorie deprivation (4). IGF type 1 receptors are present on monocytes, natural killer (NK) cells, and T helper cells (5), and IGF is believed to be essential for T cell proliferation (6, 7). Therefore, IGF-I might exert effects on the immune system. Several cytokines, including interleukin-1ß (IL-1ß) and IL-2, are important for the immune system to work properly (8). Tumor necrosis factor-{alpha} (TNF{alpha}) is increased in malnourished patients (2, 9), but the extent that other cytokines are influenced by nutritional status is not clear. Although quantification of serum concentrations of cytokines is difficult, the measurement of cytokines produced by peripheral blood mononuclear cells (PBMCs) in vitro can be used to overcome these problems and has been proposed to reflect cytokine production in vivo (2).

Our working hypothesis is that nutritional deprivation reduces not only serum concentrations of IGF-I, but also the production of cytokines important for immune function. To test our hypothesis, normal volunteers were subjected to 7 days of fasting, and PBMC production of IL-1ß, IL-2, TNF{alpha}, PGE2, IGF-I, and IGF-binding protein-1 (IGFBP-1), -2, and -3 was studied. Serum concentrations of IL-1ß, TNF{alpha}, IGF-I, and IGFBP-1, -2, and -3 were also followed. Although this study model may not mimic precisely the effects of prolonged protein-calorie malnutrition, it allows study of in vivo/in vitro events related to undernutrition without interference from various factors that complicate studies of patients with chronic malnutrition secondary to intercurrent illness.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

Ten healthy nonsmoking volunteers (four women and six men) who were taking no medication completed the study (Table 1Go). After obtaining informed consent, subjects were housed in private rooms at the General Clinical Research Center at the University of North Carolina, and their activities were strictly supervised. Oral intake, from 2300 h on day 0 (admission) through day 8 (discharge), was limited to mineral water (minimum, 2000 mL daily) and one daily tablet of multivitamins with minerals (Theragran M, Apothecon, Princeton, NJ). Blood samples were collected between 0800–0845 h on days 1 (overnight fast = prefast), 2, 4, 6, and 8 (7 days of fast = postfast) for hematological, immunological, and biochemical testing. Within 48 h, each subject developed ketonuria and began to lose weight. The average weight loss between days 1–8 was 5.5 ± 0.2 kg. All subjects experienced hunger, which lessened by day 3; two experienced nausea (days 2–3); one developed orthostatic hypotension, which resolved with increased water intake (day 2); one experienced nightly muscle cramps relieved by walking (day 4; normal electrolytes). Social and psychological problems and/or hunger caused four female subjects to withdraw from the study (days 1–4; data not included). Three age-matched healthy volunteers (women, 24 and 30 yr, and a men, 27 yr), weighing 95–115% of ideal body weight, were recruited as nonfasting control subjects.


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  		Table 1. Sex, age, height, percentage of IBW, and weight loss between day 1 (prefast) and day 8 (postfast)

 
Isolation and culture of PBMCs

PBMCs were separated over Ficoll-Paque (Pharmacia, NJ) by a modification of a technique described by van der Meer et al. (10). The interphase was washed twice (225 x g, 8 min) in RPMI 1640, and differential counts revealed more than 90% mononuclear blood cells. PBMCs were diluted with serum-free RPMI 1640 culture medium supplemented with 2 mmol/L L-glutamine, 50 U/mL penicillin, 50 mg/mL streptomycin, and 1% Nutridoma HU (Boehringer Mannheim Biochemicals, Indianapolis, IN), and 200-µL samples were aliquoted to each well of a flat-bottom, tissue culture-treated 96-well cell culture cluster (Costar, Cambridge, MA). PBMCs were challenged with phytohemagglutinin P (PHA-P; 0.1–100 µg/mL; Difco, Detroit, MI) or with endotoxin [lipopolysaccharide (LPS) extracted from Escherichia coli 055:B5; 3–3000 pg/mL; Sigma Chemical Co., St. Louis, MO] at 37 C in 5% CO2. Both secretagogues gave similar results (LPS results not shown). After culture, supernatants from 3–13 replicate wells were pooled and frozen (-80 C) for determinations of IL-1ß, IL-2, TNF{alpha}, PGE2, IGF-I, and IGFBP-1, -2, and -3. Cell viability was consistently greater than 99% throughout the culture period when tested by exclusion of trypan blue (11).

From three nonfasting control subjects, different concentrations of PBMCs (0.5–10 x 106 cells) were cultured for 24 h in the presence of PHA-P (10 µg/mL). The stimulation of IL-1ß, IL-2, TNF{alpha}, and PGE2 production was optimal when the concentration of PBMCs was 2.5 x 106 cells/mL (Fig. 1Go). To determine the optimal time of culture, PBMCs (2.5 x 106 cells/mL) were harvested after 4, 8, 16, and 24 h and daily on days 2–7. Peak concentrations of IL-2, TNF{alpha}, and PGE2 were reached after about 24 h of culture (Fig. 2Go). IL-1ß was maximal after 3 days in culture (Fig. 2Go). In all subsequent experiments, we chose to culture 2.5 x 106 PBMCs/mL for 24 h. For each of the three nonfasting control subjects, PBMC production of IL-1ß, L-2, TNF{alpha}, and PGE2 was very stable when exposed to various concentrations of LPS or PHA-P 1 week apart [P = 0.99 when comparing dose (1–100 µg/mL PHA-P)-response (IL-2) curves].



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  		Figure 1. Effect of cell density on cytokine release in vitro. PBMCs were cultured at concentrations ranging from 0.5–10 x 106 cells/mL and stimulated with PHA-P (10 µg/mL). IL-1ß, TNF{alpha}, IL-2, PGE2, and TNFß release into the medium at 24 h is shown. The vertical line indicates the PBMC concentration (2.5 x 106 cells/mL) chosen for subsequent experiments. Data are the mean of three experiments.

 


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  		Figure 2. Effect of duration of culture on cytokine release in vitro. PBMCs (2.5 x 106 cells/mL) were cultured for up to 7 days in the presence of 10 µg/mL PHA-P and harvested after 4, 8, 16, and 24 h and daily on days 2–7. The concentrations of IL-1ß, TNF{alpha}, IL-2, and PGE2 were measured in the culture medium. The vertical line at 24 h indicates the duration of culture chosen for subsequent experiments. Data are the mean ± SEM for three experiments.

 
Assays of cytokines, IGF-I, and IGFBPs

IL-1ß, IL-2, and TNF{alpha} were determined in the culture medium using the Quantikine Immuno Assays System (R&D Systems, Minneapolis, MN), which uses monoclonal antibodies that are specific and sensitive to levels of 0.3 pg/mL (IL-1ß), 6.0 pg/mL (IL-2), and 4.4 pg/mL (TNF{alpha}). Serum concentrations of IL-1ß and TNF{alpha} (measures free and bound TNF) were determined by specific high sensitivity immunoassays (R&D Systems) using monoclonal antibodies sensitive to levels less than 0.05 pg/mL (IL-1ß) or less than 0.18 pg/mL (TNF{alpha}). Immunoreactive IGF-I was measured by a highly specific nonequilibrium RIA (12) after removal of IGFBPs by C18 cartridge chromatography (Sep-Pak, Waters Associates, Milford, MA) (13). In this separating procedure, bound IGF-I is separated from the IGFBPs. Culture medium was concentrated 10 times before assay of IGF-I. IGFBP-1, -2, and -3 were measured using sensitive double antibody RIAs (14, 15, 16) with lower limits of detection of 0.2, 0.08, and 0.5 ng/mL, respectively.

Statistical analysis

Statistical analysis was performed using repeat measure one-way ANOVAs (time-course data), repeat measure two-way ANOVAs (dose-response data; SuperANOVA software from Abacus Concepts, Berkeley, CA), or paired Student’s t test (comparisons between prefast and postfast serum levels). Five levels of significance were tested: P < 0.05, P < 0.01, P < 0.005, P < 0.001, and P < 0.0001.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
One week of fasting did not affect the total white blood cell count (5.8 ± 0.4 vs. 5.4 ± 0.3 x 109/L), neutrophils (3.1 ± 0.3 vs. 2.8 ± 0.2 x 109/L), lymphocytes (1.8 ± 0.1 vs. 1.7 ± 0.1 x 109/L), or monocytes (0.36 ± 0.02 vs. 0.33 ± 0.03 x 109/L). There were, however, increases in hemoglobin (14.4 ± 0.4 vs. 15.4 ± 0.5 g/dL; P < 0.05), hematocrit (42.6 ± 1.2 vs. 44.2 ± 1.1%; P < 0.05), and platelets (246 ± 16 vs. 279 ± 19 x 109/L; P < 0.05), most likely reflecting hemoconcentration during fasting. Total serum protein (7.3 ± 0.2 vs. 8.2 ± 0.2 g/dL) and albumin (4.6 ± 0.1 vs. 5.2 ± 0.1 g/dL) increased (P < 0.001) during fasting. The distribution of T cell subpopulations in peripheral blood changed significantly during fasting (Table 2Go). The total numbers of T cells (CD3+) and T helper cells (CD4+) decreased (15 ± 3% and 17 ± 3%, respectively), whereas CD16+ and CD56+ NK cells increased (50 ± 11% and 46 ± 11%, respectively). Serum concentrations of IL-1ß and TNF{alpha} were similar prefast (0.67 ± 0.20 and 1.92 ± 0.24 pg/mL, respectively) and postfast (0.76 ± 0.22 and 2.07 ± 0.29 pg/mL, respectively). Serum PRL decreased from 20.6 ± 3.6 ng/mL (prefast) to 14.5 ± 3.8 ng/mL (postfast; P = 0.05). Serum IGF-I declined from 247 ± 29 (prefast) to 87 ± 10 ng/mL (postfast; P < 0.0001). Serum IGFBP-1 increased from 45 ± 6 ng/mL (prefast) to 248 ± 26 ng/mL (postfast; P < 0.0001), and IGFBP-2 increased from 184 ± 21 ng/mL (prefast) to 303 ± 27 ng/mL (postfast; P < 0.0001). Serum IGFBP-3 decreased from 3.1 ± 0.1 ng/mL (prefast) to 2.4 ± 0.1 ng/mL (postfast; P < 0.001).


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  		Table 2. Distribution of T cell subpopulations

 
Fasting increased PBMC production of IL-1ß (Fig. 3AGo) when stimulated with different concentrations of PHA-P [184 ± 28 vs. 293 ± 76 pg/mL in response to 3 µg/mL PHA-P; P < 0.05 when comparing dose-response curves (1–100 µg/mL PHA-P)] or LPS (data not shown). Figure 3BGo shows that fasting decreased the production of IL-2 in response to various concentrations of PHA-P [347 ± 48 vs. 135 ± 52 pg/mL when challenged with 3 µg/mL PHA-P; P < 0.005 when comparing dose-response curves (1–100 µg/mL PHA-P)]. In three subjects, PBMCs were cultured for 4 h in addition to the routine 24-h culture period. In these subjects, fasting increased IL-1ß and decreased IL-2 to the same extent independent of the duration of cultures (data not shown). Fasting did not affect the release of TNF{alpha} when PBMCs were challenged with various concentrations of PHA-P or LPS (data not shown). Fasting tended to increase PBMC release of PGE2 when stimulated with low concentrations of PHA-P (0.1, 0.3, and 1 µg/mL) or LPS (3, 10, 30, and 100 pg/mL), but this did not reach statistical significance (data not shown). When stimulated with higher concentrations of PHA-P (3, 10, and 100 µg/mL) or LPS (300 and 1000 pg/mL), PGE2 release was not affected by fasting. The concentrations of IGF-I and IGFBP-1, -2, and -3 were not measurable in culture medium by RIA.



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  		Figure 3. Effect of 7 days of fasting on IL-1ß (A) and IL-2 (B) release from 2.5 x 106 PBMCs/mL cultured for 24 h in the presence of PHA-P (0.1–100 µg/mL). Data are the mean ± SEM from 10 subjects. *, P < 0.05; **, P < 0.005 (for comparisons between curves).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In response to 7 days of fasting, we observed decreased production of IL-2 from PBMCs stimulated with PHA-P or LPS. A recent report shows that IGF-I potentiates IL-2 production in human peripheral T cells (17). It is, therefore, possible that the decreased IL-2 production seen in our fasting subjects is secondary to the depressed serum IGF-I concentration observed by us and others (4). Fasting also decreased the population of T cells known to synthesize and secrete cytokines and to be the most important source of IL-2 production (18). Our finding that IL-2 release is decreased in fasting subjects may, therefore, be at least partly explained by a decreased proportion of T helper cells. In addition, IL-2 has been shown to enhance the proliferation of PHA-P-stimulated PBMCs (19), which suggests an autocrine function for IL-2 in PBMCs.

Fasting increased the release of IL-1ß from stimulated PBMCs. IL-1ß, mainly produced by macrophages and monocytes, is one of the key mediators of the immune response to microbial invasion, immunological reactions, inflammatory responses, and tissue injury (8). A functional defect in the capacity of T lymphocytes to respond to exogenous IL-1 has been reported in malnourished rabbits (20). Therefore, it is possible that the increased production of IL-1ß in fasting subjects is an adaptive mechanism to counteract a decreased T cell responsiveness. Malnutrition has been reported to enhance the production of TNF{alpha} in humans (2, 9). This could not be confirmed in our study, but the lack of such an effect might be explained by the relatively short period of starvation.

Fasting decreased serum concentrations of IGF-I and PRL, hormones known to stimulate the proliferation of T cells (6, 7, 21). The T cell suppression observed in fasted subjects could, therefore, be secondary to reduced concentrations of IGF-I and PRL in serum. PRL also increases the expression of IL-2 receptors on T helper cells (22), further linking a classical hormone to the cytokine/immune system. The marked increase in serum concentrations of IGFBP-1 and IGFBP-2 during fasting could serve as an adaptive mechanism to increase the bioavailability of IGF-I, thereby preserving T cell proliferation during conditions of nutritional deprivation.

In malnourished patients, the in vitro basal cytotoxicity of NK cells is decreased, but can be stimulated by IL-2 or IGF-I (23, 24, 25). Our results showing that IL-2 and IGF-I are decreased in fasting subjects further supports an important role for IL-2 and IGF-I in maintaining a normal NK cell cytotoxicity. A relatively high density of type I IGF receptors has been detected on NK cells (5, 24), suggesting that the type I receptor on this cell type is functional, and IGF-I could act as a mediator of hormonal action on the immune system.

It seems unlikely that the approximately 3-fold suppression of IL-2 and the decreased IGF-I we observed could cause immunosuppression, as our model undoubtedly does not faithfully mimic chronic starvation. The prolongation of nutrient denial, however, could continue to reduce IL-2 and IGF-I so as to eventually promote immunosuppression. IGF-I and IL-2 are available for human use, thereby raising the possibility of developing a therapeutic regimen for treatment of the immunodeficiency that occurs in malnourished patients.


   Acknowledgments
 
We are grateful to research dietitian Marjorie Busby, biostatistician Dr. Keith E. Muller, and the nursing staff, all at the General Clinical Research Center, University of North Carolina at Chapel Hill. We appreciate help from Ms. Julia A. Mitchell, Center for Gastrointestinal Biology and Disease (cytokine assays); Dr. David Clemmons, Department of Medicine, (RIA of IGFBPs); and Ms. Eyvonne Bruton, Department of Pediatrics (technical support).


   Footnotes
 
1 This work was supported by NIH Research Grant R01-HD-26871, General Clinical Research Center Grant RR-00046 from the Division of Research Resources, NIH, and NIH Grant P30-DK-34987 to the Center for Gastrointestinal Biology and Disease of the University of North Carolina at Chapel Hill. Back

2 Recipient of a research fellowship from the European Society for Pediatric Endocrinology. Back

Received June 18, 1996.

Revised October 18, 1996.

Accepted December 26, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Bistrian BR, Sherman M, Blackburn GL, Marshall R, Shaw C. 1977 Cellular immunity in adult marasmus. Arch Intern Med. 137:1408–1411.[Abstract/Free Full Text]
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  4. Thissen J-P, Ketelslegers J-M, Underwood LE. 1994 Nutritional regulation of the insulin-like growth factors. Endocr Rev. 15:80–101.[Abstract/Free Full Text]
  5. Kooijman R, Willems M, Rijkers GT, et al. 1992 Effect of insulin-like growth factors and growth hormone on the in vitro proliferation of T-lymphocytes. J Neuroimmunol. 38:95–104.[CrossRef][Medline]
  6. Reiss K, Porcu P, Sell C, Pietrzkowski Z, Baserga R. 1992 The insulin-like growth factor 1 receptor is required for the proliferation of hemopoietic cells. Oncogene. 7:2243–2248.[Medline]
  7. Clark R, Strasser J, McCabe S, Robbins K, Jardieu P. 1993 Insulin-like growth factor-1 stimulation of lymphopoiesis. J Clin Invest. 92:540–548.
  8. Meydani SN. 1992 Modulation of cytokine production by dietary polyunsaturated fatty acids. Proc Soc Exp Biol Med. 200:189–193.[CrossRef][Medline]
  9. Vaisman N, Schattner A, Hahn T. 1989 Tumor necrosis factor production during starvation. Am J Med. 87:115.[Medline]
  10. van der Meer JWM, Endres S, Lonnemann G, et al. 1988 Concentrations of immunoreactive human tumor necrosis factor alpha produced by human mononuclear cells in vitro. J Leukocyte Biol. 43:216–223.[Abstract]
  11. Conn HJ. 1961 Nitro and azo dyes. In: Conn HJ, ed. Biological stains. Baltimore: Williams and Wilkins; 85.
  12. Copeland KC, Underwood LE, Van Wyk JJ. 1980 Induction of immunoreactive somatomedin-C in human serum by growth hormone: dose response relationships and effect on chromatographic profiles. J Clin Endocrinol Metab. 50:690–697.[Abstract/Free Full Text]
  13. Davenport ML, D’Ercole AJ, Underwood LE. 1990 Effect of maternal fasting on fetal growth, serum insulin-like growth factors (IGFs), and tissue IGF messenger ribonucleic acids. Endocrinology. 126:2062–2067.[Abstract/Free Full Text]
  14. Busby WH, Snyder DK, Clemmons DR. 1988 Radioimmunoassay of a 26,000-dalton plasma insulin-like growth factor-binding protein: control by nutritional variables. J Clin Endocrinol Metab. 67:1225–1230.[Abstract/Free Full Text]
  15. Clemmons DR, Snyder DK, Busby WH. 1991 Variables controlling the secretion of insulin-like growth factor binding protein-2 in normal human subjects. J Clin Endocrinol Metab. 73:727–733.[Abstract/Free Full Text]
  16. Camacho-Hubner C, Busby WH, McCusker RH, Wright G, Clemmons DR. 1992 Identification of the forms of insulin-like growth factor binding proteins produced by human fibroblasts and the mechanisms that regulate their secretion. J Biol Chem. 267:11949–11956.[Abstract/Free Full Text]
  17. Kooijman R, Rijkers GT, Zegers BJM. 1996 IGF-I potentiates interleukin-2 production in human peripheral T cells. J Endocrinol. 149:351–356.[Abstract/Free Full Text]
  18. Brenner, MK. 1994 Haematological applications of interleukin-2 and other immunostimulatory cytokines. Bailliere Clin Haematol. 7:115–134.[CrossRef][Medline]
  19. Olsen SC, Stevensens MG. 1993 Effects of recombinant human cytokines on mitogen-induced bovine peripheral blood mononuclear cell proliferation. Cytokine. 5:498–505.[CrossRef][Medline]
  20. Hoffman-Goetz L, Young KC. 1986 Modulation of cellular immunity in malnutrition:effect of interleukin 1 on suppressor T cell activity. Clin Exp Immunol. 65:381–386.[Medline]
  21. Clevenger CV, Sillman AL, Hanley-Hyde J, Prystowsky MB. 1992 Requirement for prolactin during cell cycle regulated gene expression in cloned T-lymphocytes. Endocrinology. 130:3216–3222.[Abstract/Free Full Text]
  22. Gala RR, Shevach EM. 1993 Influence of prolactin and growth hormone on the activation of dwarf mouse lymphocytes in vivo. Proc Soc Exp Biol Med. 204:224–230.[CrossRef][Medline]
  23. Villa ML, Ferrario E, Bergamasco E, Bozzetti F, Cozzaglio L, Clerici E. 1991 Reduced natural killer cell activity and IL-2 production in malnourished cancer patients. Br J Cancer. 63:1010–1014.[Medline]
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