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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3383-3390
Copyright © 2000 by The Endocrine Society

Original Studies

High-Dose Growth Hormone Does Not Affect Proinflammatory Cytokine (Tumor Necrosis Factor-{alpha}, Interleukin-6, and Interferon-{gamma}) Release from Activated Peripheral Blood Mononuclear Cells or after Minimal to Moderate Surgical Stress1

S. H. Zarkesh-Esfahani, O. Kolstad, R. A. Metcalfe, P. F. Watson, S. Von Laue, S. Walters, A. Revhaug, A. P. Weetman and R. J. M. Ross

Division of Clinical Sciences and SCHARR (S.W.), Sheffield University, Sheffield, United Kingdom S5 7AU; and Tromso University (O.K., A.R.), Tromso, Norway

Address all correspondence and requests for reprints to: Dr. Richard J. M. Ross, Clinical Sciences, Northern General Hospital, Sheffield, United Kingdom S5 7AU. E-mail: r.j.ross{at}sheffield.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
High-dose GH therapy, with GH doses 10–20 times the normal replacement dose for GH-deficient adults, has been used as an anti-catabolic agent in a number of different patient groups. A recent study, however, has shown an increase in mortality in critically ill patients treated with high-dose GH. The increased mortality was associated with multiorgan failure, septic shock, and uncontrolled infection, suggesting that GH may have altered the immune response. The GH receptor and GH are both expressed in peripheral blood mononuclear cells (PBMCs); thus, GH could act as either an endocrine or an autocrine modulator of the immune response. We have examined the hypothesis that high-dose GH therapy may induce proinflammatory cytokines, which are implicated in septic shock. To do this we measured cytokine production by PBMCs incubated in conditions that simulated high-dose GH therapy, and we measured cytokine levels in patients undergoing laparoscopic cholecystectomy who were randomized to receive either high-dose GH therapy (13 IU/m2·day) or placebo.

To confirm the biological activity of GH in our cell culture system we used a Stat5 functional assay. In this assay GH induced a bell-shaped curve, with a maximal response at GH levels between 100-1000 ng/mL. PBMCs from healthy volunteers were incubated with GH in doses from 1–1000 ng/mL for 6–72 h under resting conditions and after activation with endotoxin and the mixed lymphocyte reaction. Studies were repeated with PBMCs from six individuals using a GH dose of 100 ng/mL (the level of GH found after high-dose GH therapy) and an endotoxin dose that gave a submaximal response (0.01 ng/mL). GH had no effect on cell proliferation or the production of tumor necrosis factor-{alpha} (TNF{alpha}), interleukin-6 (IL-6), or interferon-{gamma} (IFN{gamma}). In patients undergoing laparoscopic cholecystectomy there was a time-related effect of surgery on cytokine levels. There was a rise in IL-6 and a fall in TNF{alpha} at 24 h after surgery; however, high-dose GH therapy had no effect on the cytokine response. We considered the possibility that endogenous GH production by PBMCs could influence the cytokine response in activated PBMCs; however, incubation of PBMCs in the presence of the GH receptor antagonist, B2036, had no effect on TNF{alpha}, IL-6, or IFN{gamma} production by PBMCs in either the mixed lymphocyte reaction or when activated by endotoxin.

These results suggest that high-dose GH therapy does not alter the proinflammatory cytokine response to surgery or endotoxin. The results do not exclude an effect of GH on the immune response, but they suggest that the mortality seen in critically ill patients may be due to factors other than immune modulation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HIGH-DOSE GH has been used as an anticatabolic agent in a number of conditions, including patients who have undergone surgery or suffered severe burns (1). A recent disturbing report suggests that high-dose GH treatment of critically ill patients was directly related to an increased mortality in this patient group (2). Multiple organ failure, septic shock, and uncontrolled infections were the main causes of death, suggesting the possibility that GH modulated the immune response. In animal experiments there is evidence to support the concept that in the presence of sepsis, excess GH may be a disadvantage. In septic rodents and pigs, GH potentiates the biological activities of endotoxin and has an unfavorable effect on carbohydrate metabolism (3, 4).

The GH receptor (GHR) is a member of the type 1 cytokine receptor family and is expressed on human peripheral blood mononuclear cells (PBMCs) (5). In healthy individuals most circulating B cells and monocytes are GHR positive, and there is low expression in T cells (6). GH-deficient humans show no obvious immune deficit (5); however, GH is locally produced by PBMCs (7), and therefore a pituitary deficiency may not result in immune deficiency (5).

The role of GH in immune regulation of humans is as yet undefined (8), and studies of GH administration have given varying results. GH-deficient children had basal tumor necrosis factor-{alpha} (TNF{alpha}) levels similar to controls, but GH administration caused an acute rise in TNF{alpha} levels (9). In contrast, in GH-deficient adults, basal TNF{alpha} levels were high and fell after prolonged GH administration (10). In human immunodeficiency virus (HIV) patients treated with GH there was no significant change in immune function (11), and in surgical patients treated with GH there was no change in cytokine levels (12); however, GH treatment of normal human PBMCs reduced the TNF{alpha} and interleukin-1ß (IL-1ß) production in response to endotoxin (13).

The use of GH as an anticatabolic agent and the observation that high-dose GH treatment is associated with an increased mortality due to sepsis in critically ill patients (2) emphasize the importance of investigating the action of GH on the immune system. In this study we asked the specific question of whether high-dose GH treatment promotes proinflammatory cytokine production from resting and activated human PBMCs either in culture or in patients undergoing surgical stress.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell culture

Venous blood samples (50 mL) were collected from healthy male adults (aged 20–45 yr). PBMCs were isolated by Lymphoprep, washed twice in normal saline and once in medium, and suspended in medium [RPMI 1640 supplemented with L-glutamine (2 mmol/L), penicillin/streptomycin (10 mg/mL), and 2% heat-inactivated normal human AB serum] to a density of 1 x 106/mL. For the cytokine production assay 2 mL cell suspension were transferred to each well of a 24-well plate, and for the proliferation assay 200 µL were transferred to each well of a 96-well plate. The cells were treated with different concentrations of endotoxin (lipopolysaccharide from Escherichia coli stereotype 0111:B4, Sigma, St. Louis, MO), Phytohemagglutinin (PHA; Sigma), GH (Genotropin, recombinant human GH, Pharmacia Biotech, Uppsala, Sweden), or GH antagonist B2036 (supplied by William Bennett, Sensus Drug Development Corp., Austin, TX). Incubations were performed in a humidified atmosphere containing 5% CO2. After 72-h incubation, media were centrifuged for 10 min. Cells were discarded, and the supernatants were stored at -70 C until assay. Mixed lymphocyte reactions (MLR; allostimulation) were set up using PBMCs from a responder and the same number of allogeneic irradiated (30 Gy) PBMCs from another person as stimulator. For proliferation assays 200 µL of 1 x 106/mL PBMCs were incubated for 5 days in round bottomed microplates, either unstimulated or stimulated with endotoxin, GH, or GH antagonist. For allostimulation, 100 µL PBMC were incubated with 100 µL irradiated PBMC from another person (cell ratio, 1:1). During the last 24 h, 0.1 mCi [3H]thymidine was added, and proliferation assessed from the [3H]thymidine incorporation as counts per min. All materials were screened and were negative for endotoxin.

Assays

Cytokines were measured by enzyme-linked immunosorbent assay [TNF{alpha}; R&D Systems, Oxon, UK; interferon-{gamma} (IFN{gamma}): Diaclone Research Kits, Besancon, France; IL-6: R&D Systems]; the intraassay CVs were 8.7%, 0.59%, and 4.4%, respectively. GH was measured by immunoradiometric assay (Medix Biochemica, Kauniainen, Finland).

GH treatment in vivo

Nineteen female patients [aged 19–66 yr (4 postmenopause), body mass index, 22–33 kg/m2] underwent elective laparoscopic cholecystectomy. The study design was placebo controlled, randomized, and double blind. Patients received either 13 IU/m2·day rhGH (Genotropin, recombinant human growth hormone, Pharmacia) or placebo (0.9% NaCl) at 0800 h on the day of surgery (before surgery) and then daily for 3 consecutive days. Both groups of patients received standardized total parenteral nutrition containing glutamine. Venous blood samples were collected the day before surgery and on the first, second, and third postoperative days at 1200 h. The protocol was approved by the ethical board of the Clinical Research Center at Tromso University Hospital, and the patients gave informed consent.

Functional assay

Stable clones expressing the full-length human GHR were generated in 293 cells (human kidney embryonal cell line) as previously described (14).Transcription assays were performed in the stable clone 293 cells expressing the GHR and transiently transfected with a reporter construct containing a Stat5-binding element fused to a minimal TK promoter and luciferase. Luciferase activity was measured as previously reported (15).

Statistics

The paired t test was used to compare cytokine levels in media from PBMCs and proliferation of cells. For analysis of serum levels in patients undergoing surgery, repeated measures ANOVA was used.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In vitro dose response of Stat5-luciferase reporter to GH (Fig. 1aGo)

To confirm the biological activity of our GH preparation in culture and to determine whether a GH dose response was seen with physiological levels of GH, we used a previously established functional assay (15). Essentially 293 cells stably expressing the human GHR and transiently transfected with a Stat5-luciferase reporter were tested with GH doses between 1–100,000 ng/mL culture medium (Fig. 1aGo). There was a dose response to GH at GH doses between 1–100 ng/mL, with GH levels of 100-1000 ng/mL giving a maximal response, and there was a bell-shaped shaped curve, with GH doses greater than 1000 ng/mL suppressing the Stat5 response.



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  		Figure 1. a, Dose response of luciferase activity to GH stimulation in 293 cells stably expressing the GHR transiently transfected with a Stat5-luciferase reporter construct and stimulated with varying doses of GH for 24 h. Luciferase activity is expressed as fold induction of GH-stimulated cells over unstimulated cells. Luciferase activity was corrected for the ß-galactosidase level, which was used as a transfection control. b, Dose response for the production of IL-6 by PBMCs incubated with increasing doses of endotoxin for 24 h.

 
Dose response of IL-6 production from PBMCs exposed to endotoxin (Fig. 1bGo)

Before examining the effect of GH on PBMCs activated by endotoxin, we performed a dose response to endotoxin using doses of 0.0001–100 ng/mL. Endotoxin induced production of IL-6 at doses as low as 0.001 ng/mL, and a maximal response was seen with an endotoxin dose of 0.1 ng/mL. Thus, for subsequent experiments a submaximal dose of endotoxin was used (0.01 ng/mL medium).

Effect of GH on resting PBMCs (Figs. 2Go and 3Go)

Resting PBMCs were incubated with and without GH at varying doses between 1–1000 ng/mL for 3 days, and the medium was then assayed for cytokines (Fig. 2aGo). Medium from cells incubated without GH showed very low levels of TNF{alpha}, IL-6, and IFN{gamma}, and there was no induction of the cytokines with GH doses up to 1000 ng/mL. Endotoxin (0.01 ng/mL) and PHA (5 µg/mL) induced TNF{alpha} (20- and 292-fold), IL-6 (36- and 807-fold), and IFN{gamma} (1.2- and 762-fold). Medium from cells incubated with GH was also sampled at 3, 6, 12, 24, 48, 72, and 96 h after the start of the GH incubation, and no change in cytokine level was found (data not shown). Similarly, there was no change in cell proliferation in response to increasing doses of GH, although a clear effect was seen in response to endotoxin and PHA (Fig. 2bGo). PBMCs from six separate individuals were then incubated with a GH dose (100 ng/mL) that we had previously shown to have a maximal effect on GH activation of Stat5 and was similar to the GH level found in surgical patients after GH treatment (see below). Again, GH had no effect on production of TNF{alpha}, IL-6, or IFN{gamma} (Fig. 3aGo).



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  		Figure 2. a, Mean (±SEM) levels of TNF{alpha}, IFN{gamma}, and IL-6 in medium from PBMCs from two normal subjects incubated with varying doses of GH, endotoxin (0.01 ng/mL) and PHA (5 µg/mL) for 3 days. $, IL-6 values are expressed at 10-1 to fit on the same scale as the other cytokines. *, P < 0.01 vs. unstimulated cells. b, Cell proliferation assay. Mean (±SEM) level of thymidine incorporation by PBMCs from two normal subjects incubated with varying doses of GH, endotoxin (0.01 ng/mL) and PHA (5 µg/mL) for 5 days. *, P < 0.01 vs unstimulated cells.

 


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  		Figure 3. a, Mean (±SEM) levels of TNF{alpha}, IFN{gamma}, and IL-6 in the culture medium of PBMC from six healthy individuals incubated in the absence or presence of GH (100 ng/mL) and/or endotoxin (0.01 ng/mL). b, Mean (±SEM) levels of TNF{alpha}, IFN{gamma}, and IL-6 in cells in the absence or presence GH (100 ng/mL) in a MLR using PBMCs as responders (n = 6 subjects) and MHC-mismatched PBMCs as stimulator cells.

 
Effect of GH on PBMCs exposed to endotoxin (Fig. 3aGo)

Using a dose of endotoxin that induced a submaximal IL-6 response (0.01 ng/mL) and a dose of GH known to induce a maximal response (100 ng/mL), PBMCs from six separate individuals were incubated with and without GH and endotoxin, alone or in combination. GH had no effect on the production of TNF{alpha}, IL-6, and IFN{gamma} in either the absence or presence of endotoxin.

Effect of GH on PBMCs activated by MLR (Fig. 3bGo)

PBMCs were activated by coculture with MHC-incompatible (allogeneic) stimulator cells (MLR) and were incubated with and without GH. The effects of GH were studied in experiments lasting for 1–5 days in six separate individuals with doses of GH ranging from 1–1000 ng/mL. GH had no effect on the MLR induction of TNF{alpha}, IL-6, and IFN{gamma}. MLR augmented PBMC proliferation, but this was not altered by GH (PBMCs only, 923 ± 178; MLR only, 3867 ± 372; MLR plus GH, 3594 ± 532 cpm).

The GH antagonist, B2036 (Fig. 4Go)

In case endogenous production of GH was masking any GH action, experiments were repeated with a dose of GH antagonist (B2036, 1000 ng/mL) known to completely block receptor signaling (14). The GH antagonist had no effect on cytokine production in either resting PBMCs or cells activated by incubation with endotoxin.



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  		Figure 4. Mean (±SEM) levels of TNF{alpha}, IFN{gamma}, and IL-6 in the culture medium of PBMC or MLR from four healthy individuals incubated in the absence or presence of the GH antagonist B2036 (1000 ng/mL) and/or endotoxin (0.01 ng/mL).

 
Cytokine response to surgical stress (Fig. 5Go)

Data was collected over 4 days for the 19 patients (10 GH and 9 placebo) who underwent laparascopic cholecystectomy. There was no effect of GH on any of the cytokine levels despite GH levels of 116 ± 22 ng/mL in the GH group the day after surgery and 1.7 ± 0.4 ng/mL in the placebo group. However, there was statistical evidence of a time effect after surgery for all cytokines (IL-6, P < 0.001; TNF{alpha}, P < 0.001). The IL-6 and TNF{alpha} responses followed a quadratic shape.



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  		Figure 5. IL-6 (a), and TNF{alpha} (b) levels in patients treated with GH or placebo on the day before treatment and surgery (day -1) and for 3 days after laparoscopic cholecystectomy (days 1, 2, and 3).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have examined in detail the effect of high-dose GH on PBMCs both in vitro and in vivo. GH had no effect on either resting or activated PBMC proliferation or their production of TNF{alpha}, IL-6, and IFN{gamma}. Similarly, high-dose GH treatment of patients undergoing surgical stress had no effect on the surgically induced changes in TNF{alpha} and IL-6. In these studies we were very careful in our choice of GH dose and controls. In simultaneous experiments we showed that GH, at the doses used, was biologically active in a functional assay of Stat5 induction, and that a GH level of 100 ng/mL had a maximal effect on Stat5 induction (the dose response was a bell-shaped curve, as it is now well recognized that high-doses of GH block receptor signaling) (16). All of the PBMC incubations had controls with endotoxin or PHA. PBMCs were very sensitive to incubation with endotoxin, and a level of 0.01 ng/mL induced a clear response of cell proliferation and cytokine production. The doses of GH used in the PBMC incubations were chosen to reflect those found in patients treated with high-dose GH. In the surgical patients a GH level of 116 ± 22 ng/mL (mean ± SEM) was found after GH treatment with 13 IU/m2·day GH. This dose of GH is 10–20 times the normal dose for GH replacement in adults and is similar to the dose of GH used in many studies of its anticatabolic therapy (17), including the recent study in critically ill patients (2). Our results, therefore, suggest that high-dose GH therapy is unlikely to induce PBMC proliferation or alter the production of TNF{alpha}, IL-6, or IFN{gamma}. We chose to study these cytokines because they are proinflammatory, they modulate the activation of macrophages, and they are implicated in inducing septic shock and multiple organ failure (18).

The changes in cytokine levels following surgery are determined by a number of factors, including the type of surgery and anesthetic. For example, different changes are seen in patients undergoing open vs. laparoscopic cholecystectomy (19). We chose to study patients undergoing laparoscopic cholecystectomy because these patients represent a relatively homogenous group with, therefore, a more reproducible physiological response in whom we would be likely to detect any influence of GH treatment. The surgery had a relatively minor effect on cytokine production, inducing a rise in IL-6 levels at 24 h and a fall in TNF{alpha} at 24 h. These results are broadly similar to previous observations in this patient group (19, 20), although in one study TNF{alpha} levels were higher at 24 h (21). The finding that GH had no effect on the cytokine response to surgery is consistent with results in another patient group. Patients undergoing abdominal aortic aneurysm repair were treated with high-dose GH or placebo for 6 days before surgery, and there was no difference in their IL-6 rise after surgery (12). Body mass index and estrogen status may affect cytokine levels; however, as cytokine measurements were made within the same patient before and after surgery, these variables would be unlikely to have influenced our results.

Our results do not preclude the possibility that high-dose GH has a detrimental effect on another aspect of the immune system that we have not studied and that could be implicated in the increase in mortality seen in critically ill patients (2). In addition, critically ill patients may well have other confounding factors, such as sepsis or drugs, which may interact with GH and the immune system. Previous reports, however, have generally been consistent with GH having a beneficial effect on the immune response. In patients with moderately advanced HIV infection, high-dose GH therapy was reasonably well tolerated, and there was a modest improvement in HIV-specific immune function (11). In patients undergoing cholecystectomy, high-dose GH treatment was associated with improved cell-mediated immunity and a reduced incidence of postoperative wound infection (22), although in this study the incidence of infection was surprisingly high in the placebo-treated group. Consistent with GH not influencing the immune response was the lack of effect GH had on septic episodes in children with burns (23) or on sepsis score in patients with sepsis (24). Overall, our results and the above studies suggest that the increase in mortality seen in septic animals (3, 4) and critically ill humans (2) treated with GH is not related to an effect of GH on the inflammatory response. It seems likely that the detrimental effect of GH in the presence of sepsis may well be associated with changes in the metabolic response (4).

The effects of GH on immune function in animal models of inflammation and in vitro cultures of mononuclear cells have been varied. This probably relates to experimental conditions, as in a number of studies doses of GH and endotoxin were used that greatly exceeded those found in either normal subjects or septic patients, in whom high-dose GH treatment has been used. GH has been shown to prime macrophages (25) and enhance the production of TNF{alpha} in response to endotoxin (26), but in calves GH reduced the TNF{alpha} response to endotoxin (27). GH enhanced cytokine responses and improved the survival of septic mice (28), in contrast to the previously discussed increase in mortality seen in other animal models (4). In studies of splenic lymphocytes GH at an extremely high-dose (10,000 ng/mL) increased cell proliferation and production of IFN{gamma} in mice with burn injury (29), and GH at a very low dose (0.1 ng/mL) reduced the IFN{gamma} response to treatment with staphylococcal A toxin (30), but increased the response to a very high-dose of lipopolysaccharide (500 ng/mL) (31). In human PBMCs a very high-dose of GH (500 ng/mL) inhibited the production of TNF{alpha} in response to a very high-dose of endotoxin (10 ng/mL). In our studies we used GH concentrations (100 ng/mL) that are encountered in patients receiving high-dose GH treatment and levels of endotoxin that induced a submaximal response. Under these conditions GH had no effect on cytokine production or cell proliferation. The studies were also repeated using another condition of priming and activating PBMCs, the MLR; again, under these conditions there was no effect of GH.

In view of the observation that normal replacement doses of GH in GH-deficient children (9) increased TNF{alpha} and decreased TNF{alpha} levels in adults (10), we considered the possibility that low levels of endogenous GH produced by PBMCs (7) could alter cytokine responses. To test this hypothesis we used the recently synthesized GHR antagonist, B2036. This GH mutant blocks GH-stimulated cell proliferation (16, 32, 33, 34, 35) and GH signaling (14). At doses that completely block signaling (14), the antagonist had no effect on either basal or activated PBMC cytokine production or proliferation.

In conclusion, we examined whether high-dose GH therapy induces proinflammatory cytokines and PBMC proliferation. In cell culture, under conditions that simulate high-dose GH therapy, GH had no effect on cytokine production of resting or activated PBMC. Similarly, GH had no effect on the cytokine response to surgery. These studies do not exclude the possibility that the adverse effect of GH in critically ill patients is due to a change in the immune response, but suggest that this detrimental action of GH is not due to activation of proinflammatory cytokines.


   Footnotes
 
1 This work was supported by Serono Laboratories, Inc., the Wellcome Trust, PPP Health Care, and Trent Regional Research Schemes. Back

Received January 8, 2000.

Revised May 12, 2000.

Accepted June 7, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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