Am. J. Trop. Med. Hyg., 77(2), 2007, pp. 297-302
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene
Implications of Dynamic Changes among Tumor Necrosis Factor-
(TNF-), Membrane TNF Receptor, and Soluble TNF Receptor Levels in Regard to the Severity of Dengue Infection
Lin Wang,
Rong-Fu Chen,
Jien-Wei Liu,
Hong-Ren Yu,
Ho-Chang Kuo, AND
Kuender D. Yang*
Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, Republic of China; Division of Infectious Diseases, Department of Internal Medicine, Departments of Pediatrics and Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China
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ABSTRACT
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Tumor necrosis factor-
(TNF-) and soluble TNF receptors (sTNFR1 and sTNFR2) have been implicated in infectious diseases. We investigated dynamic changes among TNF-, membrane TNF receptors (mTNFR1 and mTNFR2), and sTNFR1 and sTNFR2 levels for patients with dengue hemorrhagic fever (DHF) and those not infected during a DEN-2 outbreak in southern Taiwan in 2002–2003. Patients with DHF showed the lowest levels of mTNFR1 and mTNFR2 expression. Multivariate analysis showed that a decrease in levels of mTNFR1 expression was the only factor significantly different between patients with DHF and those with dengue fever. Moreover, lower mTNFR1 expression was significantly correlated with higher plasma TNF- levels, but not with sTNFR1 levels in patients with DHF. This finding suggests that a lower level of mTNFR1 expression in response to a higher plasma TNF- level may be a pathogenic marker for early detection of DHF.
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INTRODUCTION
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Dengue viruses (DENVs) are arthropod-borne flaviviruses that cause significant morbidity and mortality in tropical and subtropical regions of the world. There are four serotypes of dengue viruses (DENV types 1–4). Classic dengue fever (DF) is a self-limited illness characterized by fever, headache, myalgia, arthralgia, and abdominal pain. Since the 1950s, a more severe form of the disease, dengue hemorrhagic fever (DHF), has been recognized worldwide.1 Patients who develop DHF typically have initial symptoms similar to those in DF patients, but they may also develop plasma leakage manifested by hemoconcentration, ascites, and pleural effusion that may result in irreversible dengue shock syndrome. The role of viral virulence versus secondary immune enhancement in the pathogenesis of DENV infection has been debated for many years.2,3 The underlying mechanism for DHF is believed to involve activation of virus-infected macrophages resulting in the production of certain cytokines such as tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and IL-1ß.4,5 These proinflammatory cytokines are associated in vivo with an acute-phase response, and may result in liberation of chemotactic peptides and activation of vascular endothelial cells that leads to enhanced vascular permeability, which contributes to the pathogenesis of DENV infection.6
Tumor necrosis factor- is a proinflammatory cytokine already implicated in the resultant severity of many viral infections, including DENV infection.7,8 The biologic functions of TNF- are largely influenced by two distinct and structurally homologous types of TNF receptors (TNFR1 and TNFR2), referred to as type-1 (p55 or p60) and type-2 (p75 or p80) receptors, both of which exist in soluble and membrane forms.7 Soluble forms of TNFR1 and TNFR2 (sTNFR) are derived from membrane receptors (mTNFR) after cleavage in response to many of the same inflammatory stimuli that are known to induce TNF- production.9 However, a number of studies have reported inconclusive results with regard to increased TNF- and sTNFR levels for patients with DENV infection.8,10–12 The involvement of the TNF- system and its relative integrity have been reported to be of importance for improving the survivability and management of DENV infection.13 Because TNF- has a short half-life in the circulation,14 its levels at any given moment may not necessarily reflect local production in the preceding hours. Such a situation makes plasma TNF- concentrations an unsuitable predictor for the presence of DHF.
Because granulocytes are the primary cell population involved in the acute inflammatory response,15 and given that the biologic functions of TNF-, such as activation, differentiation, or killing of cells occurs through the binding of TNF- to mTNFR, we monitored mTNFR expression on granulocytes in persons with DENV infection to better understand the reactions of these persons to TNF-. We have proposed in this study that a certain dynamic change among TNF-, sTNFR, and mTNFR may be a better predictor of hemorrhagic diseases. Based upon this hypothesis, we conducted a case control-designed study to investigate altered dynamic changes among TNF-, mTNFR, and sTNFR expression as implicated by DHF. As a result of this study design, our investigations included a cohort of controls with other non-dengue febrile illnesses (OFIs), which enabled us to determine whether the observed phenomena were specific to DENV infection.
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MATERIALS AND METHODS
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Case-control study design.
A total of 69 hospitalized patients with confirmed DENV-2 infections were recruited for this study after informed consent was requested and obtained from these individuals. This study was undertaken during a DENV-2 outbreak from August 2002 through March 2003 in southern Taiwan.16,17 Study-participant blood samples were drawn between one and three days after individual admission to hospital. These patients received supportive care that included supplementation of intravenous fluid and administration of non-steroid anti-inflammatory medication for antipyretic treatment prior to obtaining the blood sample. We used a complicated and an uncomplicated case-control design for this study.18 We obtained blood samples from one to two patients with DHF, from the same number of patients with classic DF fever, from those with OFIs (presumed to be viral illness), and from age-matched healthy controls. The DENV-2 infections were confirmed by virus detection in the blood by reverse transcription–polymerase chain reaction (RT-PCR) or detection of IgM to DENV.19 Patients with DHF were defined according to the criteria of the World Health Organization for DHF; these criteria describe DF as complicated with a reduced platelet count (< 100,000/mm3), petechiae, hemorrhagic manifestations, plasma leakage showing hemoconcentration 
20%, pleural effusion, ascites, or hypoalbuminemia.20 The OFIs were defined as those illnesses in patients who had fever but no detectable DENV-specific IgM, no detectable DENV RNA in leukocytes, no obvious bacterial etiology for their illness, and were presumed to most likely have non-dengue viral illnesses.
Collection and separation of blood samples.
Five-milliliter heparinized blood samples were collected from patients who were hospitalized with suspected DENV-2 infections and were used for study purposes. The study protocol was reviewed and approved by the Institution Review Board of Chang Gung Memorial Hospital, Taiwan.21 The blood was initially separated into plasma and blood cells by centrifugation at 2,500 rpm (150 x g) for 20 minutes. Plasma was dispensed into several aliquots and storied at –80°C until used. Leukocytes were separated from erythrocytes by 4.5% dextran sedimentation as described by Chen and others.22
Measurement of plasma TNF-, sTNFR1, and sTNFR2 levels.
Plasma levels of TNF, sTNFR1 and sTNFR2 were measured using enzyme-linked immunosorbent assay (ELISA) kits (Bender MedSystems Inc., Vienna, Austria). Results were calculated from interpolation of a standard curve made from a series of known concentrations of commercial standards.22 Using such ELISA kits, we determined that the minimum detectable plasma levels of TNF-, sTNFR1, and sTNFR2 were 2.5, 80, and 160 pg/mL, respectively.
Flow cytometric analysis of mTNFR1 and mTNFR2 expression on leukocytes.
Study sample blood leukocytes were washed once with phosphate-buffered saline (PBS) and stained at room temperature in the dark with phycoerythrin (PE)–conjugated mouse monoclonal antibodies to human TNFR1 and TNFR2 (Caltag, Burlingame, CA) for 30 minutes. After removal of erythrocytes with ammonium chloride lysis buffer, leukocytes were washed with PBS, fixed with 1% paraformaldehyde, and analyzed using flow cytometry (FACS caliber; Becton Dickinson, San Jose, CA) as described.23,24 As shown in Figure 1
, granulocytes and lymphocytes were differentially gated by forward-scatter and side-scatter processes (Figure 1A). Granulocytes, but not lymphocytes, showed greater TNFR1 expression in DF patients than in DHF patients (Figure 1B and C). A total of 10,000 cells were analyzed by CellQuest software (Becton Dickinson). The level of mTNFR1 and mTNFR2 expression on the surface of lymphocytes and granulocytes was determined. Expression is presented as the percentage of positive cells gated with an unrelated PE-conjugated IgG1 staining control.
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FIGURE 1. Tumor necrosis factor receptor 1 (TNFR1) expression on the surface of granulocytes and lymphocytes from individuals with dengue fever (DF) or dengue hemorrhagic fever (DHF) by flow cytometric analysis. A, Identification of blood granulocytes was established according to a dot plot sketched by size (forward scatter) versus granularity (side scatter). B, Level of TNFR1 expression on the surface of granulocytes from DHF and DF patients. C, Level of TNFR1 expression on the surface of lymphocytes from DHF and DF patients. mTNFR1 = membrane TNF receptor 1.
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Data and statistical analysis.
Data acquired from subjects with confirmed DENV-2 infections were classified into one of two patient categories, those with DHF and those with DF. Data for detection of immune mediators are presented as the mean ± SE. The Student’s t-test was used for statistical comparisons between continuous variables, Chi-square analysis was used for comparisons between categorical variables. Spearman’s correlation was used to evaluate relationships between different immune mediators. Analysis of variance (ANOVA) and the Games-Howell test was used to analyze differences in immune mediators between study subjects and healthy controls. Multivariate logistic regression was used to examine the associations between study variables and relative disease severity. The study power was originally set at 0.8 with the level = 0.05 and the effect size = 0.25 of TNFR1 expression on the surface of granulocytes (e.g., DHF = 53.8 ± 10.6% versus DF = 67.5 ± 5.5%). Sample size was estimated at 25 DHF patients and 50 DF patients in the 1:2 case-control study.
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RESULTS
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Demographic data for patients with DHF or DF.
During a large DENV-2 outbreak in southern Taiwan between August 2002 and March 2003,16,17 we recruited 93 patients with suspected DENV-2 infections who were admitted to our hospital to participate in this study that featured a complicated versus uncomplicated case-control design. Sixty-nine of the 93 patients were shown to be infected with DENV-2 by real-time quantitative RT-PCR or by detection of DENV-specific IgM. The age of the patients studied ranged from 15 to 80 years. Of the 69 patients studied, 25 had from DHF and 44 from DF. Twenty of the 25 DHF patients had mild DHF (grades I/II) and the other five DHF patients had severe DHF (grades III/IV). The main characteristics of the study population are summarized in Table 1. There were no significant differences between patients with DHF and those with DF for age, sex, total leukocyte counts, serum levels of alanine aminotransferase and albumin, or duration of fever. Hematocrit levels, platelet counts, serum aspartate aminotransferase levels, plasma leakage including pleural effusion and ascites, and duration of hospitalization were, significantly different between patients with DHF and those who did not have DHF (Table 1).
Plasma TNF-, sTNFR1, and sTNFR2 levels in patients with DHF or DF.
The TNF- levels in blood are known to be related to certain infectious diseases.7 In contrast, certain antagonists such as sTNFR1 and sTNFR2 in the blood have been shown to modulate the biologic functions of TNF- via ligand-receptor binding.25 We measured levels of certain cytokines in the blood of patients with DHF (n = 25) and those with DF (n = 44). Results showed that plasma TNF- concentrations were detectable only in 12 (25%) of 44 DF patients compared with 8 (32%) of 25 DHF patients. Patients with DHF had greater TNF- levels than those with DF (36.57 ± 19.47 pg/mL versus 3.49 ± 0.36 pg/mL), although this difference did not reach statistical significance (P = 0.102; Table 2). Plasma sTNFR1 levels were significantly greater in patients with DHF than in those with DF (5,626 ± 1,270 pg/mL versus 2,846 ± 212 pg/mL; P = 0.040). However, plasma sTNFR2 levels were not significantly different between these two groups (12,846 ± 2,204 pg/mL versus 8,289 ± 778 pg/mL; P = 0.061; Table 2).
Granulocyte mTNFR1 and mTNFR2 expression in patients with DHF or DF.
The level of mTNFR1 expression on the surface of granulocytes differed significantly among DHF patients, those with DF, those with OFIs, and HCs (percentages of mTNFR1-positive cells were DHF = 51.61 ± 5.67%, DF = 71.45 ± 2.60%, OFIs = 79.44 ± 2.07%, HCs = 81.99 ± 1.72%; P < 0.001, by ANOVA; Figure 2A). The level of mTNFR2 expression on the surface of granulocytes also differed significantly among patients with DHF, those with DF, those with OFIs, and HCs (DHF = 67.70 ± 5.99%, DF = 83.69 ± 2.04%, OFIs = 86.11 ± 2.25%, HCs = 91.53 ± 1.54%; P < 0.001, by ANOVA; Figure 2B). The level of expression of mTNFR1 on the surface of granulocytes in DHF patients was significantly lower than that in DF patients (P < 0.016), patients with OFIs (P < 0.001), and HCs (P < 0.001). The level of expression of mTNFR2 on the surface of granulocytes in DHF patients was significantly lower than that in patients with OFIs (P < 0.039) and HCs (P = 0.005), but was not significantly lower than that in DF patients (P = 0.085). The expression of mTNFR1 and mTNFR2 on the surface of granulocytes in DF patients was significantly lower than that in HCs (P = 0.006 and 0.018), but was not significantly lower than that in patients with OFIs (P = 0.085 and 0.855). There was no significant difference between DHF and DF patients in levels of expression of mTNFR1 (17.57 ± 2.81% versus 24.35 ± 2.38%; P = 0.078) and in mTNFR2 (31.36 ± 4.80% versus 37.04 ± 3.59%; P = 0.338) on the surface of lymphocytes.
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FIGURE 2. Membrane tumor necrosis factor (mTNFR1 and mTNFR2) expression on granulocytes from healthy controls (HCs), patients infected with dengue (DEN) virus type 2, and patients with other non-dengue febrile illnesses (OFIs). The mTNFR1 and mTNFR2 levels differed significantly in patients with dengue hemorrhagic fever (DHF), those with dengue fever (DF), those with OFIs, and HCs (P < 0.001, by analysis of variance). Error bars show SE. A, Patients with DHF had the lowest mTNFR1 expression on blood granulocytes compared with patients with DF (P = 0.016), those with OFIs (P < 0.001), and HCs (P < 0.001). B, The mTNFR2 expression on blood granulocytes was significantly lower in patients with DHF than in patients with OFIs (P = 0.039) or HCs (P = 0.005), but was not significantly lower compared with patients with DF (P = 0.082).
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The mean fluorescence intensity of mTNFR1 and mTNFR2 on the surface of granulocytes (P = 0.644 and 0.580) and lymphocytes (P = 0.384 and 0.761) was not significantly different between patients with DHF and those with DF. As shown in Table 2
, the level of TNF- and sTNFR2 did not show a correlation with disease activity in dengue patients, but the plasma level of sTNFR1 showed a significant correlation with disease activity in dengue patients when analyzed by univariate analysis. When the data were interpreted by multivariate analysis, a decrease in the level of mTNFR1 was the only independent factor associated with DHF (P = 0.008; Table 2).
Correlations between plasma TNF- and sTNFR levels and granulocyte mTNFR levels in dengue patients.
Plasma concentrations of TNF-, sTNFR1, and sTNFR2, and expression of mTNFR1 and mTNFR2 on granulocytes were studied simultaneously in 69 dengue patients. Plasma concentrations of sTNFR1 show a strong correlation with corresponding values for sTNFR2 in DHF and DF patients (P = 0.001 versus P = 0.001). Similarly, mTNFR1 expression showed a modest correlation with the mTNFR2 level (P = 0.005 versus P = 0.003). As shown in Table 3, the level of mTNFR1 expression on the surface of granulocytes in patients with DHF showed a negative correlation with plasma TNF- levels (r = –0.466, P = 0.019), but mTNFR2 expression did not show a correlation with plasma TNF- levels (r = –0.326, P = 0.173). There were no correlations between plasma TNF- levels and soluble TNF receptors and plasma sTNFR levels and mTNFR levels in patients with DHF. In addition, there was no correlation between TNF- and mTNFR or sTNFR in DF patients (Table 3).
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DISCUSSION
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Although elevated plasma levels of TNF- and their soluble receptor levels have been reported in patients with DENV infections, an association with severity of illness would, to the best of our knowledge, has not been previously reported.10–12 Because sTNFR is generated by proteolytic cleavage of mTNFR and often functions as a TNF- antagonist by competing for binding sites on mTNFR,26 we investigated whether dynamic changes between TNFR and TNF- could be used as a predictor for DHF. We found that lower levels of mTNFR1 expression, but not levels of TNF- , sTNFR, or mTNFR2, correlated significantly with DHF.
Both TNFR1 and TNFR2 are involved in signal transduction of TNF-. However, functional consequences of TNFR1 signaling far outweigh those initiated by the ligation of TNF- to TNFR2.27 Both TNFR1 and TNFR2 can bind to TNF- with high affinity, but their exact role in mediating the effects of TNF- is still unknown because the two receptors differ in their intracellular signaling domains.28 Our data demonstrated that plasma sTNFR1 levels correlated with plasma sTNFR2 levels, and mTNFR1 levels correlated with mTNFR2 levels, which suggests that the functions of these receptors may be redundant. Only a limited number of cell functions have been shown to be mediated by TNFR2. For granulocytes, these two receptors have been shown to cooperate with each other in optimal responses to TNF-.29 Our results indicated that persons with DHF had lower mTNFR1 and mTNFR2 levels on the surface of granulocytes than in patients with DF when investigated by univariate analysis. However, multivariate analysis showed that the decrease in mTNFR1 expression differed significantly in patients with DHF compared with those with DF, which indicated that the mTNFR2 level was the confounding factor (Table 2).
The possible mechanisms of down-regulation of mTNFR1 expression may be related to internalization and shedding of mTNFR1. From in vitro studies, a wide variety of agents are known to induce down-regulation of TNFR, including lipopolysaccharide and TNF-.30,31 TNF- has been reported to induce internalization of TNFR1 and shedding of TNFR2.30 A rapid decrease in mTNFR on the cell surface and shedding of such receptors from the cell surface may serve to transiently desensitize cells, thereby providing a mechanism for inhibition of TNF- activity.32,33 This process may be a mechanism for self-protection of polymorphic nuclear cells from excessive TNF-–induced activation within the general circulation or at certain sites of inflammation. Our results show that down-regulation of TNFR1 expression is associated with DHF, which suggests that down-regulation of mTNFR is involved in the pathogenesis of or response to DHF.
We have demonstrated that a lower level of mTNFR1 expression in patients with DHF showed a negative correlation with plasma TNF- levels, but this was not the case for sTNFR1 levels. In general, greater sTNFR1 levels were observed in DHF patients, although such levels did not correlate with the decrease in the level of mTNFR1 expression on the surface of granulocytes in DHF patients. Such an outcome suggests that mTNFR1 shedding into sTNFR1 is not the only pathway that contributes to down-regulation of mTNFR1 expression in patients with DHF; internalization of mTNFR1 after TNF- ligation may also be involved. In the light of these observations, exploring the mechanisms of mTNFR1 internalization and shedding might provide the basis for prevention of DHF through preservation of functional mTNFR1 expression.
Understanding the cellular and molecular mechanisms of TNF-–TNFR interactions may provide the potential to prevent deaths in persons with DHF. A recent animal-model study with an antibody to TNF has shown a reduction in deaths caused by DENV infections.13 Our results suggest that simultaneous measurement of plasma TNF- and mTNFR levels may serve as an early predictor of DHF, and this further highlights a potential approach to prevent DHF by modulating the interaction between TNF- and mTNFR1.
Received November 13, 2006.
Accepted for publication May 1, 2007.
Acknowledgments: We thank Dr. Eng-Yen Huang for assistance with statistical analysis and M.S. Hau Chuang for technical assistance.
Financial support: This study was supported in part by grants NSC93-2314-B-182A-010 and NSC95-2314-B-182A-042-MY2 from the National Science Council, Taiwan.
* Address correspondence to Kuender D. Yang, Department of Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China. E-mail: yangkd{at}adm.cgmh.org.tw 
Authors’ addresses: Lin Wang, Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China and Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China, Telephone: 886-7-731-7123 extension 8795, Fax: 886-7-733-8009, E-mail: wanglin{at}adm.cgmh.org.tw. Rong-Fu Chen, Department of Biological Sciences, National Sun Yatsen University, Kaohsiung, Taiwan, Republic of China, Telephone: 886-7-731-7123 extension 8857, Fax: 886-7-7312867. Jien-Wei Liu, Department of Internal Medicine, Division of Infectious Diseases, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China, Fax: 886-7-7320402. Hong-Ren Yu and Ho-Chang Kuo, Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China, Telephone: 886-7-731-7123 extension 8848, Fax: 886-7-7312867. Kuender D. Yang, Departments of Pediatrics and Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China.
Reprint requests: Kuender D. Yang, Department of Medical Research (12F12L), Chang Gung Memorial Hospital-Kaohsiung Medical Center, No. 123, Ta Pei Road, Niao Sung Hsiang, Kaohsiung 833, Taiwan, Republic of China, Telephone: 886-7-731-7123 extension 8848, Fax: 886-7-7312-867, E-mail: yangkd{at}adm.cgmh.org.tw.
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ABSTRACT
INTRODUCTION
