Ann Thorac Surg 2006;81:2196-2201
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Induction of Interleukin-19 and Interleukin-22 After Cardiac Surgery With Cardiopulmonary Bypass
Chung-Hsi Hsing, MD
a
,
d
,
Mei-Yi Hsieh, MS
b
,
Wei-Yu Chen, MS
c
,
Edmund Cheung So, MD
c
,
d
,
Bor-Chih Cheng, MD
c
,
e
,
Ming-Shi Chang, PhD
a
,
f
,
*
a Institute of Biopharmaceutical Sciences, Tainan, Taiwan
b Institute of Biochemistry and Molecular Biology, Tainan, Taiwan
c Institute of Basic Medical Sciences, Medical College, National Cheng Kung University
d Department of Anesthesiology,Tainan, Taiwan
e Department of Surgery, Tainan, Taiwan
f Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
Accepted for publication January 26, 2006.
* Address correspondence to Dr Chang, Graduate Institute of Biochemistry and Molecular Biology, National Cheng Kung University, College of Medicine, Tainan, 704 Taiwan (Email: mschang{at}mail.ncku.edu.tw).
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Abstract
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BACKGROUND: Interleukin (IL)-19, IL-20, and IL-22, three novel cytokines in the IL-10 family, have recently been discovered. The biological functions and clinical implications of these cytokines are not clear. We aimed to analyze if serum levels of these cytokines were altered in inflammatory responses of postoperative cardiopulmonary bypass (CPB) and investigate the molecular mechanism involved in cytokine induction.
METHODS: Twenty-five patients undergoing elective aortic-coronary bypass grafting with CPB were enrolled in this study. Blood samples withdrawn at (T1) before anesthesia, (T2) CPB start, (T3) CPB end, (T4) 4 hours post-CPB, (T5) 8 hours post-CPB, (T6) 12 hours post-CPB, (T7) 24 hours post-CPB, and (T8) 48 hours post-CPB were assayed for IL-6, IL-10, IL-19, IL-20, IL-22, and tumor necrotic factor-
(TNF-). Transcripts of IL-19, IL-20, and IL-22 from monocytes were analyzed. In vitro, levels of IL-19, IL-20, and IL-22 production in monocytes incubated with IL-6 and TNF- were determined.
RESULTS: The serum levels of IL-19 and IL-22 significantly increased at T3, peaked at T5, and remained increased at T8 (p<0.001). Induction of IL-19 and IL-22 was concomitant with the change in IL-10, IL-6, and TNF- levels. Interleukin-19, IL-20, and IL-22 transcripts in monocytes from patients increased after CPB. In vitro experiments showed that IL-6 and TNF- upregulated IL-19 protein expression in monocytes.
CONCLUSIONS: Serum IL-19 and IL-22 were induced in cardiac surgery with CPB and concomitant with induction of IL-6 and TNF-. The IL-19 and these proinflammatory cytokines may interactively contribute to systemic inflammatory responses after CPB.
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Introduction
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Cardiac surgery with cardiopulmonary bypass (CPB) induces the release of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) [1, 2], interleukin (IL)-1ß [2], IL-6, and IL-8 [3, 4], which have been associated with the development of systemic inflammatory response syndrome [5, 6]. Interleukin-10, which was discovered more than a decade ago and is one of the most important immunoregulative cytokines [7–9], is also induced after CPB and may be important in limiting post-CPB complications [10, 11].
Recently five novel cytokines with similar molecular structures related to IL-10 have been discovered: (1) IL-19, (2) IL-20, (3) IL-22, (4) AK-155, and (5) melanoma differentiation associated gene-7 (MDA-7) [7–9]. These are secreted alpha helical proteins with amino acid sequences up to 30% identical to that of IL-10; they contain identical positions for cysteine that reveal a structure very similar to that of IL-10. Because of these homologies, they are classified as the IL-10 family cytokines [12, 13]. Our knowledge of the biological functions of these novel IL-10 homologues is still fragmentary. Several studies point out the proinflammatory properties of IL-19, IL-20, and IL-22 [14–17]. Interleukin-19 induces monocytes to produce IL-6 and TNF- [14] and CD4+ T cells to produce Th2 cytokines, which are associated with asthma [15]. Interleukin-20 is an important effector in skin inflammation [16]. Interleukin-22 induces acute phase reactants in the liver and pancreas and is involved in the inflammatory processes [17]. However, there is no report demonstrating the functions of these cytokines in acute systemic inflammation or perioperative stress reaction.
The pattern of established post-CPB pro-inflammatory and anti-inflammatory cytokines has been clarified. The role of the recently discovered cytokines IL-19, IL-20, and IL-22 in post-CPB inflammatory responses is unknown. Therefore our goal was to assess the changes in serum levels of these cytokines in inflammatory response after cardiac surgery with CPB. Furthermore, we investigated the function of monocytes in producing these cytokines. A better understanding of the process of post-CPB systemic inflammatory response syndrome may lead us to consider new forms of intervention.
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Material and Methods
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Patients
After approval by our institutional review board (IRB: CMFHR9404-003; April 30, 2005) and receiving the patients' consent, 25 patients undergoing elective aortic-coronary bypass grafting with CPB between May 2005 and July 2005 were enrolled in this study (Table 1). Entry criteria included patients with three-vessel disease, stable angina pectoris, and no clinically significant pre-existing pulmonary disease, renal dysfunction, or hepatic dysfunction. Patients with preoperative signs of infection (white blood cell count greater than 11,000/µL, body temperature>38°C, or C-reactive protein>6 mg/L) were excluded.
Cardiopulmonary Bypass Management
Identical anesthesia and monitoring were used in each patient. The extracorporeal circuit consisted of a roller pump, a right atrial two-stage cannula for venous drainage, membrane oxygenator, and a 40-mm arterial line filter with arterial return to the ascending aorta. Before CPB, 300 U/kg heparin and additional boluses of 50 U/kg were given if necessary to maintain an activated clotting time of at least 480 seconds. Routine CPB priming consisted of lactate (1,500 mL), 20% mannitol (150 mL), 8.4% sodium bicarbonate (60 mL), and heparin (8,000 units). Cardiopulmonary bypass was performed under moderately hypothermic conditions (28°C) with flow rate adjusted to the calculated cardiac index of 2.4 L/min/m2. Potassium-based warm blood cardioplegia followed by cold blood cardioplegia was intermittently administered for myocardium protection. Patients were weaned off CPB when their rectal temperature had reached 36°C. Heparin was neutralized with protamine sulfate on discontinuation of CPB. In the intensive care unit, patients were weaned off mechanical ventilation when they met the following criteria: patient obeys commands and has stable and adequate hemodynamics; no significant arrhythmia; a body temperature>36°C; chest tube drainage of<50 mL/hour for 4 consecutive hours; urine output>1 mL/kg/hour; arterial blood pH>7.30; arterial carbon dioxide pressure<50 mm Hg; arterial oxygen pressure>90 mm Hg; and a fraction of inspired oxygen<50%. All of our patients were uneventful during the perioperative course. Postoperative ventilation time was 18.6 ± 4.5 hours. Days in the intensive care unit were 2.5 ± 0.5 (Table 1).
Blood Samples
Blood samples for detecting cytokines were withdrawn from a radial artery catheter at different time points: (T1) before anesthesia, (T2) CPB start, (T3) CPB end, (T4) 4 hours post-CPB, (T5) 8 hours post-CPB, (T6) 12 hours post-CPB, (T7) 24 hours post-CPB, and (T8) 48 hours post-CPB. The first 5 mL of each blood sample was discarded to avoid artificial activation. The serum was prepared and stored in aliquots at –80°C before analysis. C-reactive protein levels and complete blood counts were analyzed in blood samples withdrawn at T1, T4, T6, and T8.
Monocyte and cDNA Preparation
Peripheral blood mononuclear cells were isolated from blood withdrawn at T1 and T5 using Ficoll-Paque (Pharmacia, Uppsala, Sweden) density gradient centrifugation. Monocytes were washed twice with warm medium and were allowed to adhere for 30 minutes at 37°C in a 5% carbon dioxide atmosphere. The monocytes were>95% pure, as determined by Liu's staining, and contained>98% viable cells. The nonadherent cells were then removed by washing the monocytes three more times with warm medium. Total RNA of monocytes was extracted using an isolation reagent (RNA-Bee [Tel-Test Inc, Friendswood, TX]). The synthesis of oligo(dT)21-primed first-strand cDNA was done with reverse transcriptase in a total volume of 20 µL (Becton [Dickenson Biosciences, Palo Alto, CA]).
RT-Polymerase Chain Reaction
Interleukin-19, IL-20 and IL-22 transcripts in monocytes and T cells were amplified from mRNA using reverse transcriptase (RT)-polymerase chain reaction. The sense primer (5'-gct gcg tga cca aga acc tcc tgg-3') and antisense primer (5'-tag act ctg gtg gca ttg gt-3') were used for IL-19; the sense primer (5'-aag atc agc agc ctc gcc aa-3') and antisense primer (5'-cag gta ttg aag act gga gct-3') were used for IL-20; and the sense primer (5'-agt cac cag ttg ctc gag tta-3') and antisense primer (5'-tgc tct ggt caa atg cag gca t-3') were used for IL-22. The polymerase chain reaction for IL-19 and IL-20 was performed for 30 cycles (20 seconds at 94°C, 20 seconds at 60°C, and 20 seconds at 72°C), whereas IL-22 was performed for 35 cycles (20 seconds at 94°C, 20 seconds at 60°C, and 20 seconds at 72°C). The polymerase chain reaction products were visualized on 1.5% agarose gels containing ethidium bromide. The relative quantity of polymerase chain reaction products was analyzed using the Bio-Profil program (Vilbert Lourmat, Torcy, France) and expressed as a fold-increase relative to untreated control cells.
Cell Cultures
Monocytes from the peripheral blood of healthy individuals (n = 3) were cultured at a concentration of 5 x 106 cells/mL in a 6-cm plate and then treated with 30 ng/mL of human IL-1ß, IL-6, TNF-, interferon-
(IFN-), granulocyte macrophage-colony stimulating factor (GM-CSF), and lipopolysaccharide (LPS), respectively. After 20 hours of incubation, the supernatants were collected and the production of IL-19, IL-20, and IL-22 was measured using enzyme-linked immunosorbent assay (ELISA).
ELISA
Using ELISA kits (R & D Systems, Minneapolis, MN), the serum levels of IL-6, TNF-, and IL-10 were analyzed. Concentrations of IL-19, IL-20 and IL-22 were determined using ELISA with pairs of specific monoclonal or polyclonal antibodies as previously described [15, 18]. Results are expressed as the means of duplicate assays.
Statistical Analysis
All values are expressed as mean ± standard deviation. The comparison of values at different time points after CPB with baseline values of preoperation were analyzed using the one-way analysis of variance test and followed by Dunnett's test. The comparison of in vitro monocytes IL-19 protein production levels were analyzed using Kruskal-Wallis tests followed by Dunn's post-hoc tests. Statistical significance was set at p<0.05.
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Results
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Induction of IL-10, IL-6, and TNF- After CPB
To examine the inflammatory responses in cardiac surgery with CPB, we determined the levels of proinflammatory cytokines, IL-6 and TNF-. Interleukin-10, C-reactive protein, and white blood cell count were also examined. Serum levels of IL-10, IL-6, and TNF- increased significantly at T3 (p<0.001) and peaked at T5 (Table 2). At T8, all three cytokines levels were also higher than their respective T1 levels (p<0.001). Serum C-reactive protein levels increased at T6 and T8 (p<0.001) (Table 2). White blood cell count increased at T4, T6, and T8 (p<0.001). These results indicate that the inflammatory response of the patients was evoked during T3 to T8.
IL-19 and IL-22 Were Induced After CPB
To investigate whether these newly discovered cytokines were altered in patients undergoing CPB, we analyzed the serum levels of IL-19, IL-20 and IL-22 by ELISA (Fig 1). The serum levels of IL-19 showed a significant increase at T3 (p = 0.012) and peaked at T5 with a fourfold increase greater than T1 levels (357 ng/mL vs 71 ng/mL) (p<0.001) (Fig 1A). Serum levels of IL-22 also increased at T3 (p = 0.033) and peaked at T5 with a fivefold increase greater than T1 levels (854 vs. 146 ng/mL) (p<0.001) (Fig 1B). At T8, serum IL-19 and IL-22 remained higher than at T1 (p<0.001). In contrast to the upregulation of IL-19 and IL-22 after CPB, serum levels of IL-20 showed no significant changes (Table 2).
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Fig 1. (A) Interleukin (IL)-19 and (B) IL-22 serum levels in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Blood samples were collected at 8 time points: (T1) preoperative before anesthesia, (T2) CPB start, (T3) CPB end, (T4) 4 hours post-CPB, (T5) 8 hours post-CPB, (T6) 12 hours post-CPB, (T7) 24 hours post-CPB, and (T8) 48 hours post-CPB. Serum IL-19 and IL-22 were detected using enzyme-linked immunosorbent assay with a pair of monoclonal and polyclonal antibodies against human IL-19 and IL-22, respectively. *Significant increase compared with T1 level (analysis of variance). Data are means ± standard deviation (n = 25).
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Interleukin-19-mRNA, IL-20-mRNA, and IL-22-mRNA Were Induced in the Peripheral Monocytes after CPB
We further examined whether IL-19, IL-20, and IL-22 were secreted from activated peripheral blood mononuclear cells after CPB. The RNA of the peripheral monocytes of the patients at T1 and T5 were isolated, and IL-19, IL-20 and IL-22 transcripts were analyzed with RT- polymerase chain reaction (Fig 2). Transcripts of IL-19, IL-20, and IL-22 in monocytes were higher at T5 than at T1 (Fig 2A). The relative-quantity analysis of transcripts in monocytes showed a marked increase of IL-19 (8.8-fold) and a moderate increase of IL-20 (3.1-fold) and IL-22 (3.6-fold) (Fig 2B). These results indicate that activated monocytes are one of the sources of these cytokines after CPB.
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Fig 2. (A) Interleukin (IL)-19, IL-20, and IL-22 transcripts in monocytes were upregulated 8 hours after cardiopulmonary bypass (CPB) use. reverse transcriptase-polymerase chain reaction (PCR) to detect IL-19, IL-20, IL-22, and ß-actin was performed using mRNA isolated from peripheral monocytes from 3 patients preoperatively before anesthesia for CPB (T1) and 8 hours after CPB (T5). (B) The relative quantity of PCR products was analyzed using the Bio-Profil program and expressed as a fold increase relative to T1. The figure represents the expression pattern from 3 patients with similar results.
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Interleukin-6, TNF-, IFN-, GM-CSF, and LPS Upregulated the Production of IL-19 by Monocytes In Vitro
To further investigate the association of the alteration of IL-19 and other inflammatory cytokines after CPB, we performed an in vitro assay to analyze the effect of inflammatory cytokines on the expression of IL-19 in resting monocytes. In the culture media, IL-19 protein production from monocytes was increased when incubated with IL-6 (p = 0.005), TNF- (p = 0.036), IFN- (p<0.001), GM-CSF (p<0.001), and LPS (p = 0.005) (Fig 3).
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Comment
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The inflammatory response that occurs during CPB use has often been referred to as a systemic inflammatory response syndrome similar to sepsis. Previous studies [1–6] have shown that IL-6, IL-8, and TNF- are major proinflammatory cytokines released during CPB. Here we demonstrated that two novel cytokines, IL-19 and IL-22, were also induced during CPB in coronary artery bypass grafting patients. The induction of serum IL-19 and IL-22 increased at T3, peaked at T5 and persisted to T8 (Fig 1), which was concomitant with the increase in serum IL-6, IL-10 and TNF- levels (Table 2). Although there was no other major complication in our patients, our report serves as the first examination of the normal behavior of expression of these molecules after coronary artery bypass grafting with CPB.
The clinical implications of IL-19 and IL-22 have been explored very recently and are only reported in regional or chronic inflammatory diseases [15, 19, 20]. In the present report, IL-19 and IL-22 were also involved in post-CPB acute systemic inflammation concomitant with significant leukocytosis and increased C-reactive protein, IL-6, and TNF-.
The pattern of post-CPB changes in IL-10, IL-6, and TNF- levels in our report is similar to those in other cytokine studies [11, 21, 22]. However, the increased levels of IL-10, IL-6, and TNF- are more prominent than in previous reports [21, 22]. Because levels of cytokines correlate strongly with the duration of ischemia [10], tissue trauma, and endotoxin release during CPB [23, 24]. We believe that our results may be attributable in part to different durations of CPB, to different levels of surgical stress, and to the lack of steroids given to our patients. Another possibility of higher increased level of cytokines may be due to different plastic ware and water sources used in the ELISA system, which has been mentioned by R & D Systems, the commercial supplier of the ELISA system.
Our data also showed the pattern of post-CPB changes in expression levels of IL-19 and IL-22 and were similar to those of IL-10 as well as IL-6 and TNF- (Fig 1, Table 2). The interaction of IL-10 with IL-19 and IL-22 has been discussed recently [25, 26]. Interleukin-10 is induced in IL-19-stimulated peripheral blood mononuclear cells. Lipopolysaccharide-induced IL-19 expression is also regulated by IL-10. Interleukin-22 both activated the signal transducer and the activator of transcription 3, and it induced IL-10 in the epithelial cells of the colon, and was involved, perhaps functionally, in intestinal inflammation [27]. Whether IL-10 expression in vivo regulates IL-19 and IL-22 production needs further investigation.
Interleukin-19, IL-20, and IL-22 are produced primarily by immune cells [8, 12, 28]. Our data showed that IL-19, IL-20, and IL-22 transcripts were upregulated in post-CPB monocytes (Fig 2). Therefore these activated monocytes secreted the cytokines that constitute one of the sources of these cytokines increased in the circulation after CPB use. However, IL-20 protein did not increase significantly after CPB (Table 2). Alternatively, the ELISA system to detect IL-20 may not be sensitive enough to detect the low level increase of IL-20 in the serum. Thus, IL-20 may play a minor role in post-CPB systemic inflammation.
We found that IL-19 transcripts in post-CPB monocytes were markedly increased (Fig 2). We speculate that monocytes are one of the important sources of IL-19 production after CPB. We also found that IL-6, TNF-, IFN-, GM-CSF, and LPS upregulated IL-19 from resting monocytes in vitro (Fig 3), demonstrating that IL-19 is downstream of the cascade activities of IL-6, TNF-, IFN-, and GM-CSF. The induction of IL-19 by these cytokines was not caused by LPS endotoxin contamination, because the effect was abolished when these cytokines were heat-denatured before treatment (data not shown). Our previous study showed that IL-19 induced IL-6 and TNF- production resulting in cell apoptosis through TNF- [14]. Thus, the present data indicate that there is a bidirectional stimulatory effect between IL-19 and either IL-6 or TNF-. We speculate that post-CPB cytokines induction is not only by extracorporeal circulation, ischemia-reperfusion injury, release of endotoxin, and tissue trauma, but also by cytokines interaction with each other. It has been suggested that IL-6 and TNF- may contribute to myocardial dysfunction and hemodynamic instability post-CPB [10, 11, 29]. Whether IL-19 directly deteriorates cardiopulmonary dysfunction remains to be explored. We hypothesize that the interaction of these proinflammatory cytokines may be involved in systemic inflammation after cardiac surgery with CPB, and that the bidirectional stimulatory effect between IL-19 and either IL-6 or TNF- may contribute to myocardial dysfunction and hemodynamic instability after CPB. If this is the case, an antagonist against IL-19 may be used as a potential therapy aimed at interfering with the inflammatory response.
In summary, we have demonstrated that serums IL-19 and IL-22 were induced in cardiac surgery with CPB and that they were concomitant with the induction of IL-10, IL-6, and TNF-. Monocytes are one of the sources of IL-19 production after CPB. Proinflammatory cytokines such as TNF- and IL-6 induce production of IL-19 from monocytes in vitro, demonstrating that IL-19 and these proinflammatory cytokines may interactively contribute to post-CPB inflammatory responses.
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Acknowledgments
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This work was supported by grant no. CMFHR9457 from Chi-Mei Medical Center, Tainan, Taiwan.
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Abstract
Introduction
