Journal of Applied Physiology AJP: Heart and Circulatory Physiology
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J Appl Physiol 96: 597-603, 2004. First published September 23, 2003; doi:10.1152/japplphysiol.00090.2002
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Interferon-{gamma} increases monocyte HLA-DR expression without effects on glucose and fat metabolism in postoperative patients

Jesse de Metz,1 Johannes A. Romijn,2 Erik Endert,3 Mariette T. Ackermans,3 Gerrit Jan Weverling,4 Olivier R. Busch,5 Laurence Th. de Wit,5 Dirk J. Gouma,4 Ineke J. M. ten Berge,6,7,8 and Hans P. Sauerwein1

1Department of Endocrinology and Metabolism, 6Department of Clinical Immunology and Rheumatology, and 7Renal Transplant Unit, Division of Internal Medicine, 8Clinical Immunology Laboratory, 3Laboratory of Endocrinology, Department of Clinical Chemistry, 4Department of Clinical Epidemiology and Biostatistics, 5Division of Surgery, Academic Medical Center, 1100 DD Amsterdam; and 2Department of Endocrinology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Submitted 4 February 2002 ; accepted in final form 29 May 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Tissue injury is associated with decreased cellular immunity and enhanced metabolism. Immunodepression is thought to be counteracted by interferon (IFN)-{gamma}, which increases human leukocyte antigen (HLA)-DR expression. Hypermetabolism could be enhanced by IFN-{gamma} because cytokines induce a hypermetabolic response to stress. In healthy humans, IFN-{gamma} enhanced HLA-DR expression without effects on glucose and fat metabolism. In the present study, we evaluated whether IFN-{gamma} lacks potential harmful side effects on metabolic and endocrine pathways while maintaining its beneficial effects on the immune system under conditions in which the inflammatory response system is activated. In 13 patients scheduled for major surgery, we studied HLA-DR expression on peripheral blood monocytes before surgery and postoperatively randomized the patients into an intervention and a placebo group. Subsequently, we evaluated the effects of a single dose of IFN-{gamma} vs. saline on short-term monocyte activation, glucose and lipid metabolism, and glucose and lipid regulatory hormones. HLA-DR expression on monocytes was restored from postoperative levels of 54% (42-60%; median and interquartiles) to 92% (91-96%) 24 h after IFN-{gamma} adminstration but stayed low in the placebo-treated patients. IFN-{gamma} did not affect glucose metabolism (plasma glucose, rate of appearance and dissappearance of glucose) and lipid metabolism (plasma glycerol, plasma free fatty acids, and rates of appearance and disappearance of glycerol). IFN-{gamma} had no effect on plasma cortisol, adrenocorticotropic hormone, growth hormone, insulin, C-peptide, glucagon, epinephrine, and norepinephrine concentrations. We conclude that IFN-{gamma} exerts a favorable effect on cell-mediated immunity in patients after major surgery without effects on glucose and lipid metabolism.

hormones; stable isotopes; trauma; cytokines; human leukocyte antigen

TISSUE INJURY IS ASSOCIATED with decreased expression of human leukocyte antigen (HLA)-DR on monocytes (2, 15, 16, 20, 22, 37). Low levels of HLA-DR on monocytes are an ominous prognostic factor in the recovery of surgical patients, because reduced HLA-DR expression (or a defective antigen presentation or cellular immunity) is correlated with increased postoperative complications and mortality (18). Downregulation of HLA-DR expression on monocytes may partly be related to a surgically directed shift of the T helper (Th) 1/Th2 balance toward a dominating Th2-type immune response (6). Compared with preoperative production, postoperatively stimulated peripheral blood mononuclear cells produce significantly more Th2 cytokine interleukin (IL)-4 than its Th1 counterpart interferon (IFN)-{gamma} (6, 24).

Administration of IFN-{gamma} enhances the expression of HLA-DR on monocytes in vitro and in vivo (17). Several small- to intermediate-sized clinical trials have addressed the effect of IFN-{gamma} on HLA-DR expression and clinical recovery after sepsis (21) and severe injury (8, 11, 28, 38). These studies suggest that administration of IFN-{gamma} to surgical patients could have positive effects on postoperative recovery and prevention of complications, although the data are ambiguous at present (10, 25).

In addition to the reduction in cellular immunity, another potentially harmful side effect of surgical interventions is the metabolic response to stress (26, 39). This response, which is characterized by catabolic reactions, such as increases in glucose production, lipolysis, and protein turnover, is mediated by the interaction between hormones, inflammatory mediators, and the central nervous system (13, 30). Administration of inflammatory mediators like TNF-{alpha}, IFN-{alpha}, IL-2, or IL-6 to humans mimics the catabolic changes observed after tissue injury, with specific effects for each individual cytokine (4, 33, 36). In a previous study (7), our laboratory administered recombinant human (rh) IFN-{gamma} (100 µg/m2 sc) to healthy subjects in a saline-controlled crossover study with measurements of HLA-DR expression on monocytes and endocrine and metabolic parameters. IFN-{gamma} induced a profound increase in HLA-DR expression on monocytes, whereas, in contrast to other cytokines tested in a comparable setting, IFN-{gamma} exerted surprisingly small endocrine and metabolic effects.

Considering these observations, IFN-{gamma} seems to be an ideal cytokine to improve the cellular immune function in surgical patients without an additional negative influence on an activated metabolic and endocrine system. However, our observations in healthy subjects do not exclude a possible deviated endocrine and/or metabolic reaction to IFN-{gamma} in surgical patients. For instance, IFN-{gamma} may act synergistically with the many inflammatory response proteins that abundantly circulate in postoperative patients (9, 27, 34). The question arises, therefore, whether IFN-{gamma} also lacks harmful side effects on the metabolic and endocrine pathways under conditions in which the host inflammatory response system is activated, while maintaining its beneficial effects on the immune system. To our knowledge, no studies have been published in which acute metabolic, endocrine, and immunological effects of IFN-{gamma} administration are studied simultaneously in a homogeneous surgical patient population.

In patients scheduled for major surgery [pylorus-preserving pancreaticoduodenectomy (pppd)], we evaluated HLA-DR expression on peripheral blood monocytes before surgery. Postoperatively, patients were randomized into an intervention (IFN-{gamma}) and a control (saline) group. Subsequently, we evaluated the effects of a single dose of rhIFN-{gamma} (Immukine, 100 µg/m2 sc) vs. saline on short-term monocyte activation and on metabolic and endocrine parameters.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
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Experimental Subjects

Between December 1998 and December 1999, 24 patients entered the study. All patients were scheduled for elective pppd aimed at curative treatment of a suspicious tumor in the pancreatic head, papilla of Vater, distal bile duct, or duodenum. Exclusion criteria were 1) any other diseases than the currently treated disorder (including diabetes mellitus associated with the primary disease); 2) jaundice at hospital admission (bilirubin levels of >40 µM, preoperative biliary drainage was accepted); 3) fever in the 2 wk before hospital admission; 4) any medication at admission to the hospital (except for paracetamol, pancreatic enzyme supplement, or sleep medication); 5) irresectability as a peroperative finding and, therefore, deviation of the intended pppd procedure toward a bypass procedure; and 6) clinical instability or evidence of infection on the day of the study (the second postoperative day).

All patients gave written, informed consent in accordance with the Helsinki Declaration of Human Rights. The study was approved by the Research Committee and the Medical Ethical Committee of the Academic Medical Center, Amsterdam, The Netherlands.

Study Design

One day before the surgical procedure, blood was sampled for measurement of HLA-DR expression on monocytes and routine biochemical and hematologic measurements (including bilirubin). From 6:00 PM on the preoperative day until 5:00 PM on the second postoperative day, patients were only permitted to drink water in accordance with the protocol for this surgical procedure.

During surgical intervention, patients were anesthesized by using isoflurane and sufentanyl supplemented with drugs provided with the discretion of the anesthesiologist. Moreover, a high thoracic epidural catheter was inserted, through which Marcaine was administered. At the first postoperative day, patients were transferred from the recovery room to the general surgical ward. From 12:00 AM on the first postoperative day until 5:00 PM on the second postoperative day, intravenous infusion fluids were limited to saline. Oral food supply or usage of the feeding jejunostomy was only allowed from 6:00 PM on the second postoperative day onward, according to the treatment protocol. Analgesics were prescribed according the standard hospital protocol (paracetamol, morphine, and epidural Marcaine). Additionally, all patients received Fraxiparin (Sanofi, Maassluis, The Netherlands) and Sandostatin (Novartis Pharma Bazel).

On the second postoperative day, patients were randomized into either the IFN-{gamma} or control group by balanced assignment. At 6:45 AM, a catheter was placed retrogradely into an antecubital vein for sampling of venous blood. The blood was arterialized by placement of the forearm in a thermoregulated (65°C) Plexiglas box during the 20 min before blood was sampled. Another catheter, situated already in the contralateral hand vein or a central venous catheter, if available, was used for infusion of stable isotope tracers. Both catheters were kept patent by infusion of NaCl 0.65% (30 ml/h).

At 7:00 AM, blood was sampled for determination of background isotope enrichment. Subsequently, a primed (17.6 µmol/kg), continuous (0.22 µmol·kg-1·min-1) infusion of [6,6-2H2]glucose (CIL, Andover, MA) and a primed (1.5 µmol/kg), continuous (0.1 µmol·kg-1·min-1) infusion of [1,1,2,3,3-2H5]-glycerol (CIL) were started and continued until the end of the first study day [time (t) = 8 h]. At t = -10 and -5 min, and just before rhIFN-{gamma} or saline administration, blood samples for determination of isotope enrichment of [6,6-2H2]glucose and [1,1,2,3,3-2H5]glycerol were drawn. Blood samples for baseline values of plasma hormones, substrates, cytokines, and HLA-DR expression on monocytes were drawn just before rhIFN-{gamma} or saline solution was administered. At 9:00 AM (t = 0 h), rhIFN-{gamma} (100 µg/m2, Immukine, Boehringer Ingelheim, Ingelheim/Rhein, Germany) or a comparable volume of saline solution was injected subcutanously in the upper leg. At 1, 2, 4, 6, and 8 h after injection of rhIFN-{gamma} or saline, blood was drawn for the measurement of isotope enrichment, hormone, substrate, and cytokine concentrations. Twenty-four and 48 h after the injection of rhIFN-{gamma} or saline, blood was drawn for determination of plasma IFN-{gamma} levels. Blood samples taken at 8 and 24 h after administration of rhIFN-{gamma} were also analyzed for HLA-DR expression on monocytes. Blood pressure (Riva Rocci method, brachial artery), pulse rate (palpation of radial artery), and oral temperature (Terumo digital clinical Thermometer C11, Terumo, Tokyo, Japan) were recorded on the first study day at the blood-sampling time points.

Assays

All measurements of each individual subject were performed in the same run and tested in duplicate, with the exception of flow cytometric analysis, which was performed immediately after blood sampling.

Plasma glucose concentrations and enrichment were determined according to Reinhauer et al. (29), using xylose as internal standard. The gas chromatography column used was a J&W DB-17 capillary column (30 x 0.25 mm, film thickness 0.25 µm) (J&W, Folsom, CA) on an HP 6890 Series gas chromatograph coupled to an HP 5973 mass selective detector (Hewlett-Packard, Palo Alto, CA). Mass spectra were recorded at a mass-to-charge ratio of 187 for glucose and 189 for 6,6-2H2-glucose. The internal standard was monitored at a mass-to-charge ratio of 145. Plasma glycerol concentrations and enrichment were determined as described previously (1).

Free fatty acid (FFA) concentrations in plasma were determined by using the NEFA C kit (code no. 994-75409 E) from Wako Chemicals (Neuss, Germany). Plasma insulin concentration was measured by RIA [Insulin RIA 100, Pharmacia Diagnostic, Uppsala, Sweden; intra-assay coefficient of variation (CV) 3-5%, interassay CV 6-9%], and C-peptide was measured by RIA (RIA-coat c-peptide, Byk-Sangtec Diagnostics & KG, Dietzenbach, Germany; intra-assay CV 4-6%, interassay CV 6-8%). Glucagon was determined by RIA (Linco Research, St. Charles, MO; detection limit 15 ng/l, intra-assay CV 3-5%, interassay CV 9-13%). Cortisol was measured by using a luminescence enzyme immunoassay, Immulite (Cortisol, Diagnostic Products, LA; intra-assay CV 5.8%, interassay CV 7.0%), adrenocorticotropic hormone (ACTH) by immunoluminometric assay (Nichols Institute, Los Angeles, CA; intra-assay CV 4.3%, interassay CV 5.4%), growth hormone by immunoluminometric assay (Nichols Institute; detection limit 1 mU/l, intra-assay CV 7.3, interassay CV 9.6%). Catecholamines were measured by in-house HPLC method. Norepinephrine (interassay CV 13%, intra-assay CV 6%) and epinephrine (interassay CV 14%, intra-assay CV 7%) were selectively isolated by liquid-liquid extraction and derivatized to fluorescent components with 1,2-diphenylethylenediamine. The fluorescent derivatives were separated by reversed-phase liquid chromatography and detected by fluorescence detection (31, 35)

IFN-{gamma} was measured by using an in-house sandwich ELISA with a detection limit of 31 pg/ml with monoclonal antibody (mAb) MD2 as capture and biotinylated MD1 as detecting mAb, with a detection limit of 31 pg/ml. Monocyte HLA-DR expression was measured by using flow cytometry as described previously (7). Cells were incubated with anti-HLA-DR mAbs directly labeled with FITC (Becton Dickinson, San Jose, CA). Irrelevant mouse mAbs directly labeled with FITC (Becton Dickinson) were used as control for background staining. Data acquisition was performed on a FACScan flow cytometer (Becton Dickinson). Monocytes were gated by forward- and side-scatter parameters.

Calculations and Statistics

Data are presented as median values with 25th and 75th percentiles. Glucose and glycerol rate of appearance (Ra; representing endogenous glucose and glycerol production), and glucose and glycerol rate of disappearance (Rd; representing glucose and glycerol disposal) were calculated by using Steele's equation for non-steady-state conditions adapted for stable isotopes

where I is the constant tracer infusion rate (mg·kg-1·min-1), PCTp(t) is the percent enrichment in plasma glucose or glycerol taken as the average of two consecutive samples, p is the pool fraction, V is the distribution volume of glucose (165 ml/kg) or glycerol (235 ml/kg), G(t) is the plasma glucose or glycerol concentration taken as the average of two consecutive samples, and dPCTp(t)/dt is the rate of change of percent enrichment in plasma (min-1).

To test changes in the laboratory parameters over time within and between groups, data were analysed by using analysis of repeated measures by the Proc Mixed procedure of the SAS statistical software release 8.02. Proc Mixed was used to apply analysis of repeated-measures modelling fixed and random effects taking into account the covariance of the analyzed variables. Except for temperature and glucagon concentrations, this statistical test was performed after logarithmic transformation of the parameters to obtain normal distribution. A P value of <0.05 was considered to represent statistical significance. Only data from subjects who completed the entire study were used for analysis.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
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 ACKNOWLEDGMENTS
 REFERENCES
 
Patient Characteristics

Initially, 24 patients were included in the study. Postoperatively, 10 patients were excluded from the study because the tumor was irresectable with concomitant deviation of the pppd procedure. One other patient was excluded on the second postoperative day before IFN-{gamma}/saline was administered because of cardiac and respiratory instability. Thirteen other patients continued the study on the second postoperative day and were randomly assigned to the placebo or intervention group. Seven patients received 100 µg/m2 rhIFN-{gamma} subcutaneously, whereas six other patients received a similar volume of isotonic saline. Clinical characteristics of these patients are given in Table 1.


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  		Table 1. Patient characteristics

 

Clinical Effects of IFN-{gamma}

In both study arms, the incidence of clinical symptoms as chills, nausea, and headache was comparable. There were no differences between the two study arms in baseline body temperature, which were 36.9°C (36.5-37.6°C) and 37.3°C (36.7-37.5°C) for the IFN-{gamma} and control groups, respectively. In both groups, there was a small but statistically significant increase in body temperature (P = 0.002), which was highest in the IFN-{gamma} group [P = 0.053 at t = 8 h, 38.3°C (37.5-38.3°C)]. During hospital admission, one patient in each group suffered from an infectious complication but recovered after treatment with antibiotics.

IFN-{gamma} Levels

Preoperative and baseline IFN-{gamma} levels fluctuated around the lower limit of detection of our assay (31 pg/ml). During the control study, no changes from baseline levels were detected. After injection of rhIFN-{gamma}, IFN-{gamma} serum levels gradually increased to a peak level of 108 pg/ml (90-127 pg/ml). Twenty-four hours after rhIFN-{gamma} administration, IFN-{gamma} levels were back to baseline.

Monocyte Activation

HLA-DR. Preoperatively, HLA-DR expression on peripheral blood monocytes in the 13 patients who completed the study was 94% (91-96%) (Fig. 1). On the second postoperative day, just before injection of IFN-{gamma}, monocyte HLA-DR expression decreased to 54% (42-60%) and 39% (37-47%) for the intervention and control study, respectively. This decrease did not differ between the two groups. After the intervention, the monocyte HLA-DR expression did not change over time in the control group (P = 0.13), whereas in the IFN-{gamma} group the monocyte HLA-DR expression increased to 92% (91-96%) at t = 24 h (P < 0.0001), which was different from the control group (P < 0.001).



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  		Fig. 1. Effects of interferon (IFN)-{gamma} vs. saline on the percentage of human leukocyte antigen (HLA)-DR-positive monocytes in surgical patients. Preoperative (pre O) and postoperative (post O) data are separated by the dashed line. Postoperative samples were taken just before (0) and 8 and 24 h after the administration of 100 µg/m2 recombinant human (rh) IFN-{gamma} (solid bars, n = 7) or saline (open bars, n = 6). Data are expressed as medians (bars indicate the 25th and 75th percentiles). Postoperatively, monocyte HLA-DR expression did not change over time in the control group (P = 0.13), whereas in the IFN-{gamma} group monocyte HLA-DR expression increased (at time = 24 h; P < 0.0001), which was different from the control group (P < 0.001).

 

Hormones

There were no differences between the two groups in baseline levels of ACTH, cortisol, insulin, C-peptide, glucagon, growth hormone, epinephrine, and norepinephrine (Table 2). After IFN-{gamma}/saline administration, there were no significant changes in hormone levels within the groups, and no differences were measured over time between the groups.


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  		Table 2. Baseline levels of plasma hormones, substrates of energy metabolism, and glucose and glycerol kinetics

 

Substrates of Energy Metabolism and Glucose and Glycerol Kinetics

Glucose. Baseline values of glucose Ra and Rd of glucose did not differ between the two study groups (Fig. 2). There was no effect of IFN-{gamma} on plasma glucose levels, and there were no differences measured in time between both study groups. There was a significant decline, which was most marked in the first study hour, in both Ra and Rd of glucose in the IFN-{gamma} and control groups (P = 0.0001, change within group for both Ra and Rd after IFN-{gamma}), whereas there were no differences over time between the IFN-{gamma} and control group.



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  		Fig. 2. Effects of IFN-{gamma} vs. saline on glucose metabolism. Plasma glucose concentration (top) and rate of appearance (Ra; middle) and disappearance (Rd; bottom) of glucose after 100 µg/m2 rhIFN-{gamma} ({bullet}; n = 7) or saline ({circ}; n = 6) administration to postoperative patients. Data are expressed as medians (bars indicate the 25th and 75th percentiles).

 

Fat. Baseline values of plasma FFA, plasma glycerol, and Ra and Rd glycerol did not differ between the two study groups (Fig. 3). There was no effect measured in time on plasma FFA and glycerol levels within the groups or between the groups. For Ra and Rd glycerol levels, there was no effect of IFN-{gamma} in time within the group, although there was a significant difference in time between the IFN-{gamma} and control group (P < 0.05 for both Ra and Rd of glycerol).



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  		Fig. 3. Effects of IFN-{gamma} on fat metabolism. Shown are the plasma free fatty acid (FFA) and glycerol concentrations, and the Ra and Rd of glycerol after 100 µg/m2 rhIFN-{gamma} ({bullet}; n = 7) or saline ({circ}; n = 6) administration to postoperative patients. Data are expressed as medians (bars indicate the 25th and 75th percentiles).

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
In the present study, we evaluated, in postoperative patients, the short-term effects of IFN-{gamma} on immunological, endocrine, and metabolic parameters. The surgical intervention induced a reduction of monocyte HLA-DR expression that was restored by IFN-{gamma}. IFN-{gamma} did not induce effects on plasma glucose levels, glucose turnover, or glucoregulatory hormone concentrations. Moreover, IFN-{gamma} had no effect on parameters of lipolysis. Therefore, similar to results obtained in healthy volunteers (7), IFN-{gamma} induced no significant metabolic effects in surgical patients. Finally, a single dose of IFN-{gamma} (100 µg/m2) did not induce significant clinical side effects in these postoperative patients.

The present study is the first study in which preoperative and postoperative levels and the effects of IFN-{gamma} administration on HLA-DR expression on monocytes were measured in one combined study. Enhanced levels of HLA-DR expression on monocytes after IFN-{gamma} injection compared with controls have been described previously in postoperative patients with colon cancer, in severely injured patients, and in septic patients (21, 23, 40). In contrast to the present study, in none of these studies were measurements performed before (elective) trauma or disease. In the patients with colon cancer, IFN-{gamma} treatment (200 µg/day) was started 3-4 wk after curative elective surgery, and HLA-DR expression was measured after 1 mo of treatment (40). In these patients, HLA-DR expression increased from 88% at baseline to 97% after 1 mo of treatment, whereas postoperative HLA-DR expression stayed low in the control group during the total follow-up period of 12 wk. In trauma patients receiving IFN-{gamma} (100 µg/day), HLA-DR levels on monocytes before treatment with IFN-{gamma} were 57% and increased to 76% after 2 days of treatment with IFN-{gamma} (23). In septic patients, HLA-DR expression on monocytes before treatment was 27%, and IFN-{gamma} (100 µg/day) increased HLA-DR expression to 62% within 24 h (21). Our patients presented with HLA-DR expression levels after surgery that were intermediately reduced (50% 2nd postoperative day) but reached higher levels of expression 24 h post-IFN-{gamma} (93%). In all these studies including our own, IFN-{gamma} clearly increased HLA-DR expression, reflecting a significant recovery of monocyte function. The effect of exogenous IFN-{gamma} on monocytes in postoperative patients was obtained despite significantly lower peak levels in plasma IFN-{gamma} compared with our healthy subjects (7). Because the dose of IFN-{gamma} was equal in both studies, it must be concluded that the clearance of IFN-{gamma} is increased after surgery, a finding that has also been described for other mediators like insulin (5).

Cytokines are thought to play an important role in the metabolic response to injury (39). Administration of cytokines like TNF-{alpha}, IL-6, and IFN-{alpha} in humans induces a hypermetabolic state, which is reflected by cytokine-specific elevations in resting energy expenditure and increases in glucose and glycerol turnover (4, 33, 36). IFN-{gamma}, commonly marked as an important proinflammatory cytokine, was regarded to have a comparable effect on hormones and metabolism (3). In healthy humans, however, IFN-{gamma} only induced a limited increase in resting energy expenditure and did not affect glucose metabolism (7). Again, in the present study in surgical patients, IFN-{gamma} induced no significant effects on endogenous glucose production or glucoregulatory hormone levels compared with saline administration. The initial decline in both Ra and Rd of glucose in the intervention and control studies seems not to be mediated by glucoregulatory hormones, because no changes from baseline hormone levels were observed. Therefore, the phenomenon that might be a postoperative effect of the surgical procedure is possibly mediated by paracrine factors or the neuroendocrine system. In addition, in the present study, IFN-{gamma} also lacked a clear effect on lipolysis. The difference in Ra and Rd of glycerol in time between the IFN-{gamma} and control group is probably due to relatively high baseline levels in the control subjects and a subsequent regression to the mean during the study within this group. This consideration is based on recent data from our research group. In patients who underwent major surgery as treatment for esophagus cancer (n = 11 measurements on the 2nd postoperative day), Ra levels were very comparable to those of the IFN-{gamma} group: 3.5 (2.7-4.0) µmol·kg-1·min-1 (P. H. Bisschop, unpublished observations). This explanation seems to be more attractive than a possible IFN-{gamma}-induced block that prevents a surgery-induced decrease in Ra and Rd of glycerol. To our knowledge, there are no data (in vitro and in vivo) that describe a IFN-{gamma}-induced decrease of lipolytic parameters; on the contrary, in vitro relatively high dosages of IFN-{gamma} would increase lipolysis in cultured adipocytes (12). However, our observation that IFN-{gamma} does not effect lipolysis in surgical patients is in agreement with our data obtained in healthy volunteers, in which IFN-{gamma} did not affect FFA plasma levels (7) or Ra glycerol (J. de Metz, unpublished data). Therefore, IFN-{gamma} does not seem to be an important mediator of fat metabolism in humans.

Previous human studies reported the effects of IFN-{gamma} on hypothalamic-pituitary-adrenal axis activation. Increased cortisol release was unanimously found in these studies, whereas data on modulation of ACTH release are contradictory (7, 14, 19, 32). The studies in which no ACTH increase was measured preceding a cortisol peak suggest the possibility of an ACTH-independent effect of IFN-{gamma} on the adrenal glands (19, 32). In the present study, no effects of IFN-{gamma} on ACTH or cortisol levels could be detected. High baseline cortisol levels in postoperative patients may explain this lack of IFN-{gamma} effect on plasma cortisol levels. The absence of an effect on ACTH in the present study may be due to the absence of an effect of IFN-{gamma}, i.e., plasma IL-6, a known stimulator of ACTH release (33), on the mediator, which could account for ACTH release in the previous studies.

It cannot be deduced from our study to what extent IFN-{gamma} administration will result in improvement in clinical outcome. In three randomized trials, IFN-{gamma} administration to severely injured (trauma/burn) or sepsis patients did not result in definitive improvement in clinical relevant end points. Nevertheless, there is reason to believe that high-risk patients might benefit from adjuvant IFN-{gamma} therapy (10, 11, 28, 38).

We conclude that IFN-{gamma} exerts a favorable effect on cell-mediated immunity in patients after major surgery. Moreover, in surgical patients, IFN-{gamma} does not have measurable clinical, endocrine, or metabolic side effects.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
J. A. Romijn is supported by the Netherlands Organisation for Scientific Research and the Dutch Diabetes Foundation.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank the Laboratory of Endocrinology for excellent analytical support. Furthermore, we thank Richard Reijneke and Frank van Diepen for skillful technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. P. Sauerwein, Dept. of Internal Medicine, F5-170, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands (E-mail: H.P.sauerwein{at}amc.uva.nl).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Ackermans MT, Ruiter AF, and Endert E. Determination of glycerol concentrations and glycerol isotopic enrichments in human plasma by gas chromatography/mass spectrometry. Anal Biochem 258: 80-86, 1998.[CrossRef][Web of Science][Medline]
  2. Brune IB, Wilke W, Hensler T, Feussner H, Holzmann B, and Siewert JR. Normal T lymphocyte and monocyte function after minimally invasive surgery. Surg Endosc 12: 1020-1024, 1998.[CrossRef][Web of Science][Medline]
  3. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 332: 1351-1362, 1995.[Free Full Text]
  4. Corssmit EP, Heijligenberg R, Endert E, Ackermans MT, Sauerwein HP, and Romijn JA. Endocrine and metabolic effects of interferon-alpha in humans. J Clin Endocrinol Metab 81: 3265-3269, 1996.[Abstract]
  5. Dahn MS, Lange MP, Mitchell RA, Lobdell K, and Wilson RF. Insulin production following injury and sepsis. J Trauma 27: 1031-1038, 1987.[Web of Science][Medline]
  6. Decker D, Schondorf M, Bidlingmaier F, Hirner A, and von Ruecker AA. Surgical stress induces a shift in the type-1/type-2 T-helper cell balance, suggesting down-regulation of cell-mediated and up-regulation of antibody-mediated immunity commensurate to the trauma. Surgery 119: 316-325, 1996.[CrossRef][Web of Science][Medline]
  7. De Metz J, Sprangers F, Endert E, Ackermans MT, ten Berge IJM, Sauerwein HP, and Romijn JA. Interferon-{gamma} has immunomodulatory effects with minor endocrine and metabolic effects in humans. J Appl Physiol 86: 517-522, 1999.[Abstract/Free Full Text]
  8. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, and Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 3: 678-681, 1997.[CrossRef][Web of Science][Medline]
  9. Doherty GM, Lange JR, Langstein HN, Alexander HR, Buresh CM, and Norton JA. Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha. J Immunol 149: 1666-1670, 1992.[Abstract]
  10. Dries DJ. Interferon-gamma therapy for infectious complications of injury: a called third strike? Crit Care Med 26: 419-420, 1998.[CrossRef][Web of Science][Medline]
  11. Dries DJ, Jurkovich GJ, Maier RV, Clemmer TP, Struve SN, Weigelt JA, Stanford GG, Herr DL, Champion HR, Lewis FR, et al. Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial. Arch Surg 129: 1031-1042, 1994.[Abstract/Free Full Text]
  12. Feingold KR, Doerrler W, Dinarello CA, Fiers W, and Grunfeld C. Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis. Endocrinology 130: 10-16, 1992.[Abstract/Free Full Text]
  13. Gelfand RA, Matthews DE, Bier DM, and Sherwin RS. Role of counterregulatory hormones in the catabolic response to stress. J Clin Invest 74: 2238-2248, 1984.[Web of Science][Medline]
  14. Goldstein D, Gockerman J, Krishnan R, Ritchie J Jr, Tso CY, Hood LE, Ellinwood E and Laszlo J. Effects of gamma-interferon on the endocrine system: results from a phase I study. Cancer Res 47: 6397-6401, 1987.[Abstract/Free Full Text]
  15. Haupt W, Riese J, Mehler C, Weber K, Zowe M, and Hohenberger W. Monocyte function before and after surgical trauma. Dig Surg 15: 102-104, 1998.[CrossRef][Web of Science][Medline]
  16. Hensler T, Hecker H, Heeg K, Heidecke CD, Bartels H, Barthlen W, Wagner H, Siewert JR, and Holzmann B. Distinct mechanisms of immunosuppression as a consequence of major surgery. Infect Immun 65: 2283-2291, 1997.[Abstract]
  17. Hershman MJ, Appel SH, Wellhausen SR, Sonnenfeld G, and Polk HC Jr. Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients. Clin Exp Immunol 77: 67-70, 1989.[Web of Science][Medline]
  18. Hershman MJ, Cheadle WG, Wellhausen SR, Davidson PF, and Polk HC Jr. Monocyte HLA-DR antigen expression characterizes clinical outcome in the trauma patient. Br J Surg 77: 204-207, 1990.[Web of Science][Medline]
  19. Holsboer F, Stalla GK, von Bardeleben U, Hammann K, Muller H, and Muller OA. Acute adrenocortical stimulation by recombinant gamma interferon in human controls. Life Sci 42: 1-5, 1988.[CrossRef][Web of Science][Medline]
  20. Klava A, Windsor A, Boylston AW, Reynolds JV, Ramsden CW, and Guillou PJ. Monocyte activation after open and laparoscopic surgery. Br J Surg 84: 1152-1156, 1997.[CrossRef][Web of Science][Medline]
  21. Kox WJ, Bone RC, Krausch D, Docke WD, Kox SN, Wauer H, Egerer K, Querner S, Asadullah K, von Baehr R, and Volk HD. Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch Intern Med 157: 389-393, 1997.[Abstract/Free Full Text]
  22. Livingston DH, Appel SH, Wellhausen SR, Sonnenfeld G, and Polk HC Jr. Depressed interferon gamma production and monocyte HLA-DR expression after severe injury. Arch Surg 123: 1309-1312, 1988.[Abstract/Free Full Text]
  23. Livingston DH, Loder PA, Kramer SM, Gibson UE, and Polk HC Jr. Interferon gamma administration increases monocyte HLA-DR antigen expression but not endogenous interferon production. Arch Surg 129: 172-178, 1994.[Abstract/Free Full Text]
  24. Mack VE, McCarter MD, Naama HA, Calvano SE, and Daly JM. Dominance of T-helper 2-type cytokines after severe injury. Arch Surg 131: 1303-1308, 1996.[Abstract/Free Full Text]
  25. Mock CN, Dries DJ, Jurkovich GJ, and Maier RV. Assessment of two clinical trials: interferon-gamma therapy in severe injury. Shock 5: 235-240, 1996.[Web of Science][Medline]
  26. Nelson KM, Long CL, Bailey R, Smith RJ, Laws HL, and Blakemore WS. Regulation of glucose kinetics in trauma patients by insulin and glucagon. Metabolism 41: 68-75, 1992.[CrossRef][Web of Science][Medline]
  27. Okusawa S, Dinarello CA, Yancey KB, Endres S, Lawley TJ, Frank MM, Burke JF, and Gelfand JA. C5a induction of human interleukin 1. Synergistic effect with endotoxin or interferon-gamma. J Immunol 139: 2635-2640, 1987.[Abstract]
  28. Polk HC Jr, Cheadle WG, Livingston DH, Rodriguez JL, Starko KM, Izu, AE, Jaffe HS, and Sonnenfeld G. A randomized prospective clinical trial to determine the efficacy of interferon-gamma in severely injured patients. Am J Surg 163: 191-196, 1992.[CrossRef][Web of Science][Medline]
  29. Reinauer H, Gries FA, Hubinger A, Knode O, Severing K, and Susanto F. Determination of glucose turnover and glucose oxidation rates in man with stable isotope tracers. J Clin Chem Clin Biochem 28: 505-511, 1990.[Web of Science][Medline]
  30. Shamoon H, Hendler R, and Sherwin RS. Synergistic interactions among antiinsulin hormones in the pathogenesis of stress hyperglycemia in humans. J Clin Endocrinol Metab 52: 1235-1241, 1981.[Abstract/Free Full Text]
  31. Smedes F, Kraak JC, and Poppe H. Simple and fast solvent extraction system for selective and quantitative isolation of adrenaline, noradrenaline and dopamine from plasma and urine. J Chromatogr 231: 25-39, 1982.[Web of Science][Medline]
  32. Spath-Schwalbe E, Porzsolt F, Digel W, Born J, Kloss B, and Fehm HL. Elevated plasma cortisol levels during interferon-gamma treatment. Immunopharmacology 17: 141-145, 1989.[CrossRef][Web of Science][Medline]
  33. Stouthard JM, Romijn JA, Van der Poll T, Endert E, Klein S, Bakker PJ, Veenhof CH, and Sauerwein HP. Endocrinologic and metabolic effects of interleukin-6 in humans. Am J Physiol Endocrinol Metab 268: E813-E819, 1995.[Abstract/Free Full Text]
  34. Tengku-Muhammad TS, Hughes TR, Cryer A, and Ramji DP. Synergism between lipopolysaccharide and interferon gamma in the regulation of lipoprotein lipase in macrophages. Cytokine 11: 408-415, 1999.[CrossRef][Web of Science][Medline]
  35. Van der Hoorn FA, Boomsma F, Man in 't Veld AJ, and Schalekamp MA. Determination of catecholamines in human plasma by high-performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection. J Chromatogr 487: 17-28, 1989.[Web of Science][Medline]
  36. Van der Poll T, Romijn JA, Endert E, Borm JJ, Buller HR, and Sauerwein HP. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol Endocrinol Metab 261: E457-E465, 1991.[Abstract/Free Full Text]
  37. Wakefield CH, Carey PD, Foulds S, Monson JR, and Guillou PJ. Changes in major histocompatibility complex class II expression in monocytes and T cells of patients developing infection after surgery. Br J Surg 80: 205-209, 1993.[Web of Science][Medline]
  38. Wasserman D, Ioannovich JD, Hinzmann RD, Deichsel G, and Steinmann GG. Interferon-gamma in the prevention of severe burn-related infections: a European phase III multicenter trial. The Severe Burns Study Group. Crit Care Med 26: 434-439, 1998.[CrossRef][Web of Science][Medline]
  39. Watters J and Wilmore D. The metabolic response to trauma and sepsis. In: Endocrinology, edited by DeGroot LJ. Philadelphia, PA: Saunders, 1989, p. 2367-2393.
  40. Wiesenfeld M, O'Connell MJ, Wieand HS, Gonchoroff NJ, Donohue JH, Fitzgibbons RJ Jr, Krook JE, Mailliard JA, Gerstner JB, and Pazdur R. Controlled clinical trial of interferon-gamma as postoperative surgical adjuvant therapy for colon cancer. J Clin Oncol 13: 2324-2329, 1995.[Abstract/Free Full Text]




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