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Ann Thorac Surg 2006;82:103-109
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Is Interferon Gamma Suppression After Cardiac Surgery Caused by a Decreased Interleukin-12 Synthesis?

^a Department of Cardiovascular Surgery, Bundeswehr Central Hospital, Koblenz, Germany
^b Department of Immunology, Central Institute of the Bundeswehr Medical Service, Koblenz, Germany

Accepted for publication February 22, 2006.

^_* Address correspondence to Dr Franke, Dept. of Cardiovascular Surgery, Bundeswehr Central Hospital, Rübenacher Str.170, D-56072 Koblenz, Germany (Email: dr.axel.franke{at}t-online.de; axel1franke{at}bundeswehr.org).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: The suppression of interferon gamma (IFN-gamma) synthesis after cardiac surgery is discussed as a cause of postoperative immunosuppression that predisposes to postoperative infectious complications. Because several studies have suggested that interleukin-12 (IL-12) production by monocytes and macrophages is reduced after cardiac surgery, this might cause a decrease in IFN-gamma release. To better understand these processes, we assessed the role of IL-12 in IFN-gamma synthesis in vitro before and after cardiac surgery.

METHODS: Heparinized whole blood samples were obtained from 20 patients undergoing elective cardiac surgery preoperatively (day 0) and on the first (day 1), third (day 3), and fifth (day 5) postoperative days, and stimulated (24 hours) with staphylococcal enterotoxin B and lipopolysaccharide. Recombinant IL-12 was added at each time point investigated. Interferon-gamma, IL-12, IL-2, IL-4, and IL-5 concentrations and histocompatibility leukocyte antigen-DR (HLA-DR) expression on monocytes and macrophages were assayed by flow cytometry.

RESULTS: The HLA-DR expression, IL-12 release, and IFN-gamma synthesis were significantly reduced on day 1, day 3, and day 5. Recovery began on day 3. Interleukin-12 caused a significant increase in IFN-gamma synthesis at each time point. When IL-12 was added, IFN-gamma synthesis returned to preoperative levels on days 3 and 5.

CONCLUSIONS: The synthesis of IFN-gamma is significantly reduced after cardiac surgery. The application of IL-12 causes an increase in IFN-gamma synthesis before surgery and a return of IFN-gamma to preoperative levels within a few days after surgery. These findings suggest that postoperative suppression of IFN-gamma release is caused by a decrease in IL-12 synthesis. In addition, IL-12 has a mainly proinflammatory effect both before and after surgery.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Interferon (IFN)-gamma plays a central role in regulating the immune response after surgical trauma. It is synthesized by T-helper 1 (TH1) lymphocytes [1]. Because IFN-gamma stimulates the expression of histocompatibility leukocyte antigen-DR (HLA-DR) and the production of interleukin-12 (IL-12) by monocytes and macrophages, and inhibits TH2 lymphocytes from synthesizing IL-4 and IL-5, it also helps regulate the balance between nonspecific immune responses (monocytes and macrophages) and specific immune responses (TH lymphocytes) [2, 3]. A decrease in IFN-gamma serum levels and in the supernatants of stimulated cell cultures has been documented in patients after cardiac surgery with cardiopulmonary bypass (CPB) as has been reported for patients with sepsis [2, 4, 5]. The reduced synthesis of IFN-gamma is therefore discussed as a cause of altered immune function (immunosuppression, immune dysregulation) after cardiac surgery that predisposes to postoperative complications [6–8].

Interleukin-12 stimulates not only the synthesis of IFN-gamma by TH1 lymphocytes but also the differentiation of naive TH lymphocytes into IFN-gamma producing TH1 cells [9]. Several studies have shown that the synthesis of this cytokine is reduced after cardiac surgery [3, 10, 11]. It is not yet understood whether this is a cause or consequence of the decrease in IFN-gamma synthesis. For this reason, we investigated the hypothesis that in vitro IFN-gamma release can be normalized by the addition of exogenous IL-12 to a stimulated whole blood cell culture at different time points after cardiac surgery.

	Patients and Methods

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After having given their written informed consent, 20 patients undergoing elective cardiac surgery took part in this study, which had been approved by the local ethics committee. Only patients without known local or systemic infection or inflammation (fever, leucocytosis, tachycardia, or tachypnea), immune or central nervous system dysfunctions, congestive heart failure, exogenous hormone therapy, or malnutrition were enrolled in the study. In order to document monocyte and macrophage activity, we assayed HLA-DR expression and IL-12 release by stimulated whole blood preoperatively (day 0) and on the first (day 1), third (day 3), and fifth (day 5) postoperative days at 8:00 a.m.

We added exogenous IL-12 to stimulated whole blood to evaluate its effect on IFN-gamma release. In addition, we measured IL-4 and IL-5 in order to assess potential adverse effects of IL-12 on TH2 lymphocyte function and assayed IL-2 to determine the extent to which IL-12 stimulated the differentiation of naive lymphocytes into TH1 cells.

Patient Management
We used the same cardiopulmonary bypass and perioperative management procedures described previously [4]. Anesthesia was induced with etomidate (200 to 300 µg/kg) and fentanyl (20 to 30 µg/kg). After endotracheal intubation and muscle relaxation with pancuronium (100 to 200 µg/kg), anesthesia was maintained using fentanyl, midazolam, and isoflurane (0.4% to 1.5%).

The cardiopulmonary bypass equipment included nonpulsatile roller pumps and membrane oxygenators (Affinity, Avecor, Bellshill, Scotland). The pump was primed with a standard electrolyte solution containing 5,000 IU heparin, 1,000 mL Ringer's lactate, 500 mL NaCl 0.9%, 500 mL Biseko (Biotest, Dreieich, Germany), and 250 mL of a 15% mannitol solution (Osmofundin 15%; Braun Melsungen, Melsungen, Germany). Heparin (300 IU/kg) was administered just before vascular cannulation. After the institution of cardiopulmonary bypass at a flow rate of 2 to 2.4 L/m² per minute, the aorta was cross-clamped and a cold crystalloid cardioplegic solution was injected. After CPB, protamine was infused. All patients received 2,000,000 IU of aprotinin before the onset and 1,000,000 IU at the end of CPB to preserve platelet function. Cefazolin (3 x 1.5 g) was used for perioperative antibiotic prophylaxis.

Absolute Count of Lymphocytes in Peripheral Blood
Absolute lymphocyte counts were measured in heparinized whole blood samples. A Coulter MAXM hematology flow cytometer was used according to the manufacturer's instructions (Beckman/Coulter, Krefeld, Germany).

Expression of HLA-DR on Monocytes and Macrophages
The HLA-DR expression was analyzed using the QuantiBRITE Anti-HLA-DR phycoerythrin (PE)/anti-monocyte PerCP-Cy 5.5 system (Becton Dickinson, Heidelberg, Germany). We determined the mean number of anti-HLA-DR antibodies bound per monocyte (monoclonal antibody [mAb]/cell) in whole blood samples that were cooled and anticoagulated with ethylene diamine tetraacetic acid (EDTA) in order to minimize in vitro activation. Two-color fluorescence (cyanine dye-conjugated CD14 mAb and CD64 mAb) was used to identify monocytes. The system was set up and calibrated using QuantiBRITE PE beads in accordance with the manufacturer's recommendations. Approximately 1,000 monocyte events were acquired. Quantitative analysis was performed using QuantiCALC software, which automatically converts fluorescence intensity into the number of PE molecules bound per cell.

Whole Blood Culture
Heparinized whole blood samples (CPT tubes, Becton Dickinson) were diluted 1:2.5 with Roswell Park Memorial Institute medium containing 10% heat-inactivated fetal calf serum and 2% penicillin-streptomycin. The samples were stimulated with lipopolysaccharide (LPS, 1 µg/mL) and staphylococcal enterotoxin B (SEB, 1 µg/mL) to induce the production of IL-4, IL-5, IL-2, and IFN-gamma. Where appropriate, IL-12 (final concentration: 2 ng/mL, median effective dose: 0.8 to 1.5 ng/mL) was added.

The cultures were incubated at 37°C in a 6% carbon dioxide atmosphere. After 24 hours, supernatants were collected and stored at –80°C until assayed. All reagents were obtained from SIGMA (Deisenhofen, Germany), with the exception of recombinant IL-12 and IL-18. These cytokines were obtained from R&D Systems (Wiesbaden, Germany).

Measurements
Interleukin-2, IFN-gamma, IL-5, and IL-4 were measured using the cytometric bead array (CBA) kit from Becton Dickinson. This test has a sensitivity of 5 pg/mL. If the concentration exceeded the upper limit of the assay range (5,000 pg/mL), the supernatant was diluted in assay diluent.

Several studies were able to show that the number of macrophages and monocytes in peripheral whole blood increases under stressful conditions as a result of the activation and mobilization of these cells [6, 12], whereas the number of lymphocytes can decrease [13, 14]. Therefore, T-lymphocyte-derived cytokine concentrations (IL-2, IFN-gamma, IL-4, IL-5) were corrected to a concentration of 10³ lymphocytes/µL in order to reduce changes due to altered absolute lymphocyte counts. Interleukin-12 was assayed using a modified CBA kit. We optimized the relationship between the sample volume (we used 200 µL instead of the recommended volume of 50 µL) and the concentration of primary and secondary antibodies and were thus able to reach a sensitivity of 0.5 pg/mL.

Statistics
Data were collected and analyzed using standard computer software (Statview 5.0, Abacus Concepts, Berkeley, CA). The analysis of variance (ANOVA) test was used to identify differences within groups (time points) and between groups (different stimulations of whole blood cultures). When the ANOVA test revealed significant group differences, the Fisher protected least significant difference was used for pair-wise comparisons. If ANOVA assumptions were violated, unpaired Student t tests were used for within-group or between-group comparisons. A p value of less than 0.05 was considered significant. The results are expressed as mean ± standard error of the mean, unless otherwise indicated.

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Preoperative and Postoperative Clinical Data
Clinical and perioperative data are given in Table 1. All patients experienced an uneventful recovery; ie, there was no mortality or serious morbidity in this patient population.

View larger version (47K): [in this window] [in a new window]   Fig 1. (A) Interleukin-12 (IL-12) levels in the supernatants of patient-derived stimulated whole blood cultures (staphylococcal enterotoxin B 1 µg/mL and LPS 1 µg/mL) and (B) HLA-DR expression (mAb to HLA-DR/cell) preoperatively and during the first five postoperative days after cardiac surgery. Displayed is mean ± standard error of the mean (SEM). (Gray bar = preoperative values [mean ± SEM); = p < 0.05 vs d0. = p < 0.001 vs d0; d0 = preoperatively; d1 = first postoperative day; d3 = third postoperative day; d5 = fifth postoperative day; HLA-DR = histocompatibility leukocyte antigen-DR; mAb = monoclonal antibody.)

IFN-Gamma Release in Stimulated Whole Blood
The IFN-gamma release in SEB- and LPS-stimulated whole blood decreased at day 1 and increased again until day 5. The measured values, however, did not return to preoperative levels (Fig 2).

View larger version (27K): [in this window] [in a new window]   Fig 2. Interferon (IFN)-gamma levels (mean ± standard error of the mean [SEM]) in the supernatants of patient-derived stimulated whole blood cultures (staphylococcal enterotoxin B [SEB] 1 µg/mL and lipopolysaccharide [LPS] 1 µg/mL) with () or without () the addition of recombinant interleukin-12 (2 ng/mL) preoperatively and during the first five postoperative days after cardiac surgery. Displayed is mean ± SEM. The gray bar indicates preoperative values (mean ± SEM). (* =p < 0.05 vs d0 [whole blood stimulated only with SEB + LPS]; ** = p < 0.001 vs d0 [whole blood stimulated only with SEB + LPS].)

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
As mentioned above, IFN-gamma, which is produced primarily by TH1 lymphocytes, plays a key role in regulating immune responses. It stimulates the activity of the nonspecific immune system (eg, IL-12 synthesis and HLA-DR expression by monocytes and macrophages). In addition, it modulates the balance between nonspecific and specific immune responses by ensuring the regeneration of TH1 lymphocytes and inhibiting TH2 lymphocyte cytokine synthesis (IL-5 and IL-4) [2, 3]. Interferon-gamma and its effects are a precondition for a balanced immune response and the clinical role and importance of IFN-gamma in sepsis-related immunosuppression is generally acknowledged [2, 4, 5, 14].

Several studies have documented a decrease in IFN-gamma synthesis after cardiac operations. It is therefore being discussed in the literature whether the resulting alterations of the specific immune system increase the risk that a normal posttraumatic immune response (systemic inflammatory response syndrome[SIRS]) may develop into a complicated course with immunosuppression and sepsis [2, 4, 5, 14]. A comprehensive and accurate understanding of the regulation of IFN-gamma synthesis after cardiac surgery is thus of high clinical relevance.

We were able to show in our study that HLA-DR expression, as well as IL-12 and IFN-gamma synthesis, are reduced in stimulated whole blood cultures after cardiac surgery with CPB. These results are in line with previous studies investigating IFN-gamma, IL-12, and HLA-DR expression after cardiac surgery with CPB [6–8, 15–17]. When exogenous recombinant IL-12 was added to stimulated whole blood cultures at concentrations commonly found in the serum of patients after cardiac surgery [18, 19], IFN-gamma synthesis was significantly increased at all time points investigated and IFN-gamma levels in cell culture supernatants returned to preoperative values on the third day after surgery.

Although IL-12 has been reported in the literature to influence TH2 cell activity (IL-4 and IL-5 synthesis) [20, 9], we did not detect a change in TH2 cytokine synthesis nor did we observe an effect on IL-2 synthesis, which we consider to be an indicator of the differentiation of naive cells into TH1 lymphocytes. The idea of investigating the addition of IL-12 to stimulated whole blood from cardiac surgery patients was based on a number of studies suggesting that IL-12 synthesis is decreased in the presence of sepsis or other stressful conditions [3, 21, 22]. In addition, reduced IL-12 serum levels were successfully correlated with the incidence of postoperative complications after major trauma and cardiac surgery [10, 23]. Last but not least, the administration of IL-12 has been reported to have beneficial effects in septic models [16, 21, 24].

We conclude from our results that IL-12 plays an important role in stimulating IFN-gamma synthesis after cardiac surgery with CPB and that the reduced release of IL-12 by cells of the nonspecific immune system directly after surgical trauma causes a suppression of TH1 lymphocytes and thus of the specific immune system. From an immunologic perspective, the decrease in IL-12 synthesis might counteract an overstimulation of the immune system after surgical trauma. Because IFN-gamma synthesis is reduced postoperatively due to a lack of IL-12, there is no further stimulation of monocyte and macrophage activity. If this assumption were true, further research should be undertaken to assess factors (age, gender, previous diseases, previous medication, etc) that cause this potentially protective response to develop into prolonged immunosuppression and thus predispose to postoperative complications.

In addition, it should be investigated whether the role of IL-12 levels after surgical trauma is comparable with the immune response after, for example, endotoxemia. Dorresteijn and colleagues [25] report that the systemic administration of endotoxin to healthy volunteers caused an increase in IFN-gamma serum levels but had no effect on IL-12 serum levels. It should, of course, be borne in mind in this context that there are different mechanisms for stimulating IFN-gamma synthesis which have different effects depending on the causative event (major surgical trauma from cardiac surgery with CPB, sepsis, endotoxemia in healthy volunteers, etc) [22, 24].

From a clinical and cardiac surgical perspective, our results raise the question of whether and how IL-12 might play a therapeutic role in modulating the immune response after cardiac operations. Theoretically, it is possible to administer exogenous IL-12, enhance the expression of IL-12 after surgery, or increase the susceptibility of the target cells (especially TH1 lymphocytes) to (the lower level of) available IL-12.

A number of studies on the treatment of malignant or chronic inflammatory diseases have proved that a systemic application of IL-12 is possible [26–28]. Animal experiments, however, have shown that the systemic administration of IL-12 (with or without the additional use of IL-18) can induce severe systemic side effects such as multiorgan failure [16, 29]. It therefore appears probable that there are clear-cut limitations to the therapeutic use of IL-12 and that we need a more comprehensive understanding of the regulation and effects of IL-12 synthesis under the special conditions of cardiac surgery.

Interleukin-12 is produced by dendritic cells, monocytes, and macrophages in response to pathogens during infection or after stimulation. The release of IL-12 is dependent on differential mechanisms that regulate the expression of genes encoding IL-12, patterns of toll-like receptor expression and cross-regulation between the different cell subsets, involving cytokines such as IL-10 and IFN-gamma [30]. An inhibition of IL-12 expression is possible during surgical trauma at all levels of regulation. Mitsuhashi and colleagues [31], for example, were able to show that prostaglandin E2 inhibits IL-12 expression and that this effect can be reversed by a specific synthetic cyclooxygenase inhibitor. This finding may provide the basis for a further therapeutic approach to the perioperative use of IL-12 and, together with our own results, again highlights the need for more research into the regulation of IL-12 expression by monocytes and macrophages after cardiac operations.

Interleukin-12 induces IFN-gamma synthesis in TH1 cells by transmembrane receptors. These receptors, in turn, activate an increase in IL-12 expression through transcription factors such as nuclear factor of activated T cells protein, signal transducers and activators of transcription, and nuclear factor kappa B [32]. Theoretically, this mechanism can provide a further therapeutic option for enhancing the effects of IL-12. As far as we know, however, it has thus far not been studied in perioperative cardiac surgery patients. In the abovementioned study by Dorresteijn [25] on the effects of endotoxin on IFN-gamma synthesis, the sepsis-related alteration of IFN-gamma synthesis might be caused by impaired regulation of TH1 cells. By contrast, the immediate posttraumatic suppression of IFN-gamma synthesis after cardiac operations appears to be mediated by a decrease in IL-12 synthesis. Further research should be undertaken to improve our understanding of these regulatory mechanisms after cardiac surgery.

It is tempting to speculate that the immune system may be unable to respond adequately to a preoperative alteration of IFN-gamma expression in TH1 lymphocytes in conjunction with a postoperative decrease in IL-12 production by monocytes and macrophages and that this leads to immune dysregulation and immunosuppression or even immune paralysis after cardiac surgery. This is an attractive hypothesis that deserves careful research attention. Supportive evidence for this hypothesis is provided by clinical data that show that elderly individuals whose T-cell function is known to be decreased [33, 34] have a higher risk of postoperative complications.

Our clinical observations of postoperative cardiac surgery patients are thus in agreement with previous studies. According to our in vitro findings, IL-12 appears to be an important proinflammatory cytokine promoting IFN-gamma synthesis after cardiac surgery. In addition, it seems likely that the postoperative suppression of TH1 lymphocytes is caused by a lack of stimulating mediators (IL-12) rather than by cellular dysfunction of TH lymphocytes.

In summary, our findings suggest that the decrease in IL-12 release by monocytes and macrophages appears to be a key cause (though maybe not the only one) of TH1 cell suppression after cardiac surgery with CPB. Whereas a decrease in IFN-gamma synthesis is discussed as the cause of monocyte and macrophage dysfunction under septic conditions, TH1 cell suppression is induced by a reduced activity of monocytes and macrophages after cardiac surgery due to surgical trauma, perioperative SIRS, or CPB.

Limitations of the Study

1 Because of the small number of low risk patients investigated, the applicability of our results to a large population is limited.

2 In addition, our in vitro results can only be suggestive of the potential role of IL-12. Further research in an in vivo environment is necessary.

3 We studied a homogenous and well-documented patient population with an uneventful clinical course after cardiac surgery with CPB. We thus used a very special model of immune response after major trauma. This further limits the transferability of our results, especially to patients with postoperative complications.

4 As a result of the study design, we used only one concentration of IL-12. Although this concentration was higher than the median effective dose, we cannot make any statements about dose-dependent effects.

5 The focus of our study was on the synthesis of IFN-gamma. Although we were able to document that in vivo HLA-DR expression on macrophages and monocytes was reduced in our patient population, we cannot make any statements about whether the restoration of IFN-gamma synthesis in our model leads to an increase in HLA-DR expression.

Conclusions

1 IL-12 increases IFN-gamma synthesis preoperatively and postoperatively and thus possesses mainly proinflammatory activity before and after cardiac surgery.

2 Because it is possible to induce an increase in IFN-gamma synthesis by IL-12, the suppression of TH1 cells after CPB does not appear to be caused mainly by a functional defect of TH1 cells.

3 The in vitro application of IL-12 after cardiac surgery does not adversely affect TH2 cell function because the synthesis of IL-4 and IL-5 remains unchanged.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The authors gratefully acknowledge the excellent assistance provided by Barbara Isenberg, Liane Herter, and Yriss Wyss. This research was conducted with financial support from the Bundeswehr Medical Service.

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Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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