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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 11  |  Issue : 1  |  Page : 29-36

Differential effects of t helper-17 cytokines on the functions of granulocytes isolated from schistosoma mansoni-infected patients and healthy individuals


1 Department of Zoology, Faculty of Science, Helwan University, Helwan, Egypt
2 Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio, USA
3 Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission07-Apr-2016
Date of Acceptance28-Apr-2016
Date of Web Publication26-Jul-2016

Correspondence Address:
Soad Nady
Department of Zoology and Entomology, Faculty of Science, Helwan University, Helwan, 11790
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-4293.186781

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  Abstract 

Background and aim
The role of T helper-17 lymphocytes in the regulation of the immune response against Schistosoma soluble egg antigens is still controversial. In this study, the in-vitro effects of T helper-17 cytokines [interleukin (IL)-17 and IL-22] on granulocyte functions isolated from Schistosoma-infected patients or healthy individuals were examined.
Patients and methods
Twenty-seven Schistosoma mansoni-infected patients and 13 healthy individuals from Kasr Al-Aini Viral Hepatitis Center were enrolled in the present study. Granulocytes were isolated from whole blood of patients and controls by Ficoll–Paque density gradient for removal of the mononuclear layer and then lysis of red blood cells. Granulocytes were stimulated in vitro with soluble egg antigen in the presence of IL-17, IL-22, or both. After 24 h, the supernatants were collected for the measurement of tumor necrosis factor (TNF)-α, hydrogen peroxide (H2O2), myeloperoxidase (MPO), and nitric oxide (NO) using enzyme-linked immunosorbent assay as surrogate markers for granulocyte functions.
Results
The results indicated that the presence of IL-17 significantly decreased (P<0.05) TNF-α, H2O2, MPO, and NO production by granulocytes isolated from Schistosoma-infected patients. In contrast, in the presence of IL-22 or both IL-17 and IL-22, there were significant increases in the production of H2O2 and TNF-α by granulocytes isolated from Schistosoma-infected patients. Moreover, in the presence of both IL-17 and IL-22, nonsignificant changes were observed in MPO or NO levels compared with those in the control participants.
Conclusion
IL-17, in contrast to IL-22, inhibited the functional activity of granulocytes isolated from S. mansoni-infected patients. Therefore, neutralization of IL-17 may work as a therapeutic strategy for these patients.

Keywords: cytokines, granulocytes, Schistosoma spp, T helper-17 cells


How to cite this article:
El-Shorbagy A, Shata M T, Mohey MA, Nady S. Differential effects of t helper-17 cytokines on the functions of granulocytes isolated from schistosoma mansoni-infected patients and healthy individuals. J Arab Soc Med Res 2016;11:29-36

How to cite this URL:
El-Shorbagy A, Shata M T, Mohey MA, Nady S. Differential effects of t helper-17 cytokines on the functions of granulocytes isolated from schistosoma mansoni-infected patients and healthy individuals. J Arab Soc Med Res [serial online] 2016 [cited 2019 Sep 17];11:29-36. Available from: http://www.new.asmr.eg.net/text.asp?2016/11/1/29/186781


  Introduction Top


Schistosomiasis, an infectious disease caused by parasitic Trematodes (schistosomes), is a major public health problem in tropical and subtropical regions [1]. The disease causes health problems and labor loss, with a strong impact on socioeconomic development [2]. Approximately 207 million individuals are infected and 779 million are at risk of being infected in 76 endemic countries (mostly in Africa), leading to the loss of about 4.5 million disability-adjusted life years [1],[2],[3],[4]. In Egypt, two species, Schistosoma haematobium and Schistosoma mansoni, cause urinary and intestinal schistosomiasis, respectively [5].

Schistosoma eggs and their secreted products provide a continuous antigenic stimulus for the immune response. If these antigens are not sequestered or neutralized effectively, they can damage the affected tissues. Hepatocytes are particularly sensitive to toxins secreted by the Schistosoma eggs [6]. The lesions are mediated and orchestrated by CD4+ T cells as reported by several studies [7],[8],[9],[10].

Several studies suggested that T helper-17 (Th17) cells, a new CD4+ T-cell lineage, regulate the immune responses by secreting interleukin (IL)-17/IL-22 and thereby stimulating the production of additional proinflammatory and chemotactic molecules [11],[12],[13],[14],[15],[16],[17]. The role of Th17 cells and their secreted cytokines (IL-17 and IL-22) in the recruitment of granulocytes in the presence of Schistosoma soluble egg antigens (SEA) has been partially studied [18],[19]. IL-17 aids the recruitment of granulocytes during the inflammatory response against Schistosoma SEA and the development of granuloma. However, the effect of IL-22 is still unclear [16],[20]. In the present study, the effects of Th17 cytokines (IL-17 and IL-22) on granulocyte functional activities in vitro were studied using human granulocytes isolated from the whole blood of Schistosoma-infected and control participants. Granulocytes were stimulated with SEA in the presence of Th17 cytokines and cultured overnight. Their mediators such as tumor necrosis factor (TNF)-α, hydrogen peroxide (H2O2), myeloperoxidase (MPO), and nitric oxide (NO) were measured in the culture supernatant as surrogate markers for granulocyte functions.


  Patients and methods Top


Patients

Twenty-seven S. mansoni-infected patients (20 men with a mean age of 47.4±14.6 years and seven women with a mean age of 48±12 years) and 13 healthy individuals with no history of Schistosoma infection (four men with a mean age of 40.88±16 years and nine women with a mean age of 40.6±14.6 years) were enrolled in the present study. This study is a part of our project no. 1814 funded by Science and Technology Development Fund, Egypt, and enrolled 150 patients, most of whom were coinfected with hepatitis C virus. The present study focuses on S. mansoni monoinfected patients.

Participants were enrolled from Kasr Al-Aini Viral Hepatitis Center, Faculty of Medicine, Cairo University, from October 2013 to June 2015. All patients were subjected to a physical examination and a clinical history was obtained. All patients had a history of schistosomiasis, detection of S. mansoni ova in stool or rectal biopsy samples, and seropositivity for schistosomal antibodies (indirect hemagglutination; Femouz Laboratories, Asniéres, France). The patients enrolled in the study had no serological markers for the presence of all hepatitis viruses, cytomegalovirus infection, Epstein–Barr virus infection, or other hepatic or intestinal parasites. None of the patients had a history of habitual alcohol consumption or hepatocellular carcinoma.

Approximately 15 ml of blood was withdrawn from all the enrolled participants using ethylenediaminetetraacetic acid (EDTA) anticoagulated vacutainer tubes. The study was approved by the Research Ethics Committee of Cairo University, Egypt. All participants signed an informed consent.

Isolation of granulocytes from whole blood

Isolation of human granulocytes from whole blood was performed by the Ficoll–Paque density gradient as described by Mollinedo et al. [21]. Whole blood in EDTA anticoagulant (15 ml) was diluted 1 : 1 in phosphate buffer saline (Sigma, St Louis, Missouri, USA) and slowly layered on the Ficoll–Paque solution (Axis-Shield PoC AS, Oslo, Norway) in a sterile tube. The tubes were centrifuged at 1500 rpm for 25 min at 4°C in the cooling centrifuge (). The upper layers were discarded and the pellet-containing granulocytes and erythrocytes (around 5 ml) were collected. Erythrocytes were lysed by adding ACK lysis buffer (8.024 mg NH4Cl, 1.001 mg KHCO3, and 3.722 mg EDTA-Na2 · 2H2O were added to 1 : l of H2O) and mixing slowly by inversion for 5 min and left for 20 min to lyse erythrocytes completely. The granulocyte suspension was centrifuged at 2000 rpm for 10 min, the supernatant was discarded, and cells were washed with Dulbecco’s modified eagle medium media (). Finally, granulocytes were resuspended in Dulbecco’s modified eagle medium and 10% fetal bovine serum (HyClone, USA) and cells were counted. The viability of isolated granulocytes was greater than 98% as measured by trypan blue dye (ADWIC, Cairo, Egypt) exclusion.

Overnight cultures of granulocytes

Isolated granulocytes were stimulated by different antigens such as lipopolysaccharide (LPS) (100 ng/ml) as a positive control, SEA (1 ng/ml), or SEA in the presence of IL-17 (125 pg/ml), or IL-22 (300 pg/ml) or both IL-17 and IL-22 in a 96-well cell culture plate. The concentrations of antigens and cytokines were used according to the study of Nady and Shata [22]. Each experiment was conducted in triplicate. The cultures were maintained at 37°C in a 5% carbon dioxide incubator for 18 h. The supernatant was collected and stored in −70°C for further analysis.

Measured granulocytes mediators

NO was measured according to the method of Green et al. [23]. NO in the supernatant was assayed by the Griess reaction, which has the ability to produce a chromophore with the Griess reagent. Reading of the color changes was measured using a microtiter plate reader (Bio Tec, Winooski, USA) at dual wavelength (450 and 640 nm). A standard curve was used to measure the concentration of nitrite.

TNF-α was measured according to the method of Fossati et al. [24] using the enzyme-linked immunosorbent assay kit (BosterImmunoleader,Pleasanton, CA, USA).

H2O2 was measured using H2O2 colorimetric methods (‘Bio-diagnostic Com. Giza, Egypt) according to the method of Segal [25].

Human MPO was measured using the human MPO/MPO enzyme-linked immunosorbent assay kit (Booster Immunoleader) according to the method of Segal [25].

Statistical analysis

Statistical analysis was carried out using a t-test to compare granulocyte functions of Schistosoma-infected individuals with those of noninfected individuals using Graph Pad Prism 6 Software (GraphPad, San Diego, California, USA). The data are presented as mean±SD. Percent change from nonactivated granulocytes was calculated. Results with a P value of less than 0.05 were considered significant.


  Results Top


Tumor necrosis factor-α production by overnight activated granulocytes

The present results as shown in [Figure 1] indicated that LPS-stimulated granulocytes isolated from control participants produced significantly higher levels of TNF-α (P=0.0193) than that produced by granulocytes isolated from Schistosoma-infected patients. However, there was no significant difference in the levels of TNF-α produced in response to SEA by granulocytes isolated from either controls or Schistosoma-infected patients. In contrast, the presence of IL-17 significantly (P=0.0127) decreased the TNF-α level in Schistosoma-infected granulocytes compared with that in the control granulocytes. However, in the presence of IL-22 or both IL-17 and IL-22, highly significant (P<0.0001) levels of TNF-α were produced by Schistosoma-infected granulocytes compared with those produced by control granulocytes [Table 1].
Figure 1 TNF-α produced by granulocytes stimulated overnight with SEA in the presence of Th17 cytokines. *, significant different as compared to control subjects at P < 0.05. ***, significant different as compared to control subjects at P < 0.0001.

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Table 1 Tumor necrosis factor-α level (pg/ml) produced by granulocytes stimulated overnight with soluble egg antigen in the presence of T helper-17 cytokines

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Hydrogen peroxide production by overnight activated granulocytes

The differences in the levels of H2O2 produced by LPS-stimulated granulocytes isolated from either control participants or Schistosoma-infected patients were not statistically significant. SEA induced the release of significant (P=0.0021) levels of H2O2 from granulocytes isolated from control participants compared with that produced from Schistosoma-infected patients. In addition, the presence of IL-17 significantly (P=0.0302) inhibited the release of H2O2 by Schistosoma-infected granulocytes compared with that produced by control granulocytes. The presence of IL-22 alone had no significant effect on the levels of H2O2 produced by granulocytes isolated from either controls or Schistosoma-infected patients. A marked increase (P<0.001) was observed in the levels of H2O2 produced by granulocytes isolated from Schistosoma-infected patients compared with the controls in the presence of both IL-17 and IL-22 [Figure 2] and [Table 2].
Figure 2 Hydrogen peroxideproduced by granulocytes stimulated overnight with SEA in the presence of Th17 cytokines. *, significant different as compared to control subjects at P < 0.05. **, significant different as compared to control subjects at P < 0.001.

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Table 2 Hydrogen peroxide level (μmol/l) produced by granulocytes stimulated overnight with soluble egg antigen in the presence of T helper-17 cytokines

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Nitric oxide production by overnight activated granulocytes

LPS-stimulated granulocytes isolated from control participants produced significantly (P=0.021) higher levels of NO than those produced by granulocytes isolated from Schistosoma-infected patients. In contrast, SEA induced a significant (P=0.0053) increase in NO production by Schistosoma-infected granulocytes compared with that produced by control granulocytes. However, in the presence of IL-17, a significant (P=0.0018) inhibition in NO production was observed in Schistosoma-infected granulocytes compared with that produced by control granulocytes. In the presence of IL-22 or both IL-17 with IL-22, no significant changes in the levels of NO were produced by granulocytes isolated from either controls or Schistosoma-infected patients [Figure 3] and [Table 3].
Figure 3 NO produced by granulocytes stimulated overnight with SEA in the presence of Th17 cytokines. *, significant different as compared to control subjects at P < 0.05.

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Table 3 Nitric oxide level (μM/g) produced by granulocytes stimulated overnight with soluble egg antigens in the presence of T helper-17 cytokines

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Myeloperoxidase production by overnight activated granulocytes

No significant changes were observed in the levels of MPO produced by granulocytes isolated from either controls or Schistosoma-infected patients in response to LPS or SEA. In the presence of IL-17 alone were significant changes (P=0.0054) in the MPO levels observed in Schistosoma-infected granulocytes compared with that produced by control granulocytes [Figure 4] and [Table 4].
Figure 4 Myeloperoxidase produced by granulocytes stimulated overnight with SEA in the presence of Th17 cytokines. *, significant different as compared to control subjects at P < 0.05.

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Table 4 Myeloperoxidase level (ng/ml) produced by granulocytes stimulated overnight with soluble egg antigen in the presence of T helper-17 cytokines

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  Discussion Top


The role of Th17 cells in schistosomiasis has been partially explored in mice models [26],[27],[28],[29],[30],[31],[32],[33]; however, limited data are available in terms of human schistosomiasis. Previous studies have indicated that enhanced neutrophil recruitment and activation is an important factor in Th17 cell-mediated inflammation [16],[20]. A recent study suggested that one apparent mechanism used by Th17 cells to regulate the immunopathology is through the recruitment of granulocytes [34]. Both granulocytes and eosinophils contribute significantly toward immunopathology induced by Schistosoma SEA [35]. The aim of the present study was to examine the role of Th17 cells or their secreted cytokines (IL-17 and IL-22) in the functions of granulocytes in response to Schistosoma SEA in vitro in healthy individuals and Schistosoma-infected patients.

In the present study, LPS-stimulated granulocytes isolated from control participants produced significant levels of TNF-α and NO that were higher than those produced by granulocytes isolated from Schistosoma-infected patients, suggesting a potential defect in those granulocytes isolated from Schistosoma-infected patients. Previous studies reported that TNF-α is produced through the activation of Toll-like receptors, which are the appropriate receptors of LPS [36]. No significant changes in the levels of H2O2 or MPO were produced by LPS-stimulated granulocytes isolated from either control participants or Schistosoma-infected patients, suggesting that the activations pathways for TNF-α and NO may be different from that of H2O2 or MPO.

The current results showed that overnight stimulation of granulocytes with SEA did not induce significant levels of TNF-α in either controls or Schistosoma-infected patients. However, in the presence of IL-22 alone or both IL-17 and IL-22, significant levels of TNF-α were produced by Schistosoma-infected granulocytes compared with those produced by control granulocytes, suggesting higher sensitivity to IL-22 or IL-22+IL-17 of the granulocytes isolated from Schistosoma-infected patients compared with those from controls for TNF-α secretion. However, this sensitivity is blocked, in the presence of IL-17 alone, which significantly decreased TNF-α level in Schistosoma-infected granulocytes compared with that in control granulocytes.

The release of TNF-α is triggered by binding to one of two distinct receptors designated tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, which are differentially expressed on various cell types in normal and diseased tissues [37],[38]. Therefore, the unresponsiveness to SEA may be because SEA has no binding capacity to these receptors, whereas the presence of IL-22 enhanced this capacity and induced the production of TNF-α. In our previous work, it was observed that SEA exerted inhibitory effects on TNF-α production by granulocytes and this antigen might work on the same granulocyte receptors and may have similar activation pathways [39].

TNF-α primes the neutrophil respiratory burst; upregulates the expression of adhesion molecules, cytokines, and chemokines; and at high local concentrations, can stimulate reactive oxygen species production in adherent granulocytes [37],[40]. The oxidative pathway involves the release of NO, which is generated either by the constitutively expressed enzymes nitric oxide synthase (NOS)-1 and NOS-3 or the induced enzyme NOS-2. NOS-2 is not expressed in naive cells, but is induced by immunological stimuli such as bacterial LPS or cytokines such as TNF-α [41].

In the current study, SEA induced the release of significant levels of H2O2 from granulocytes isolated from control participants more than that produced by granulocytes isolated from Schistosoma-infected patients, which suggested a potential defect of granulocytes isolated from Schistosoma-infected patients compared with controls. However, this defect is unique to H2O2 because a significant increase in NO production by Schistosoma-infected granulocytes was observed compared with that produced by control granulocytes.

Limited studies have investigated the role of different cytokines in NO production from granulocytes. In the present study, both cytokines IL-17 with IL-22 did not induce NO production, which may possibly indicate that IL-17/IL-22 cytokines play no role in NO production in contrast to the findings reported in previous studies [42].

It is well known that neutrophil azurophilic granules contain a rich supply of the green heme enzyme MPO, which, in combination with H2O2 and chloride, constitutes a potent antimicrobial system [43]. The current results showed that nonsignificant levels of MPO were produced by granulocytes isolated from either controls or Schistosoma-infected patients in response to SEA. In contrast to our results, a recent study reported the production of high levels of MPO in Schistosoma japonicum-infected mice [44].

However, in the presence of IL-17 alone, significant levels of MPO were observed in Schistosoma-infected granulocytes compared with those produced by control granulocytes. Many studies have reported the antibacterial role of MPO, but few studies have investigated the effect of Th17 cytokines on MPO secretion by granulocytes [45]. Previous studies have reported that IL-17 plays a central role in pulmonary host defense by recruiting and inducing the activity of granulocytes in the bronchoalveolar space. Other studies showed that IL-17 increases potentially in association with neutrophilic inflammation and mucus excess, as well as dysregulation of acquired immunity [46],[47],[48].

Similar to its effect on TNF-α production in the present study, the presence of IL-17 significantly inhibited the release of H2O2 or NO by Schistosoma-infected granulocytes compared with those produced by control granulocytes. However, a marked increase in the H2O2 level and no significant changes in the levels of NO were observed in the presence of both IL-17 and IL-22. However, in the presence of IL-22 alone, no significant changes in the levels of H2O2 or NO were produced by granulocytes isolated from either controls or Schistosoma-infected patients. Previous studies reported that IL-17 exerts no effect on peroxide production by granulocytes activated with formyl-methionyl-leucyl phenylalanine for up to 2 h of activation [49]. In terms of IL-22, some studies [50],[51] indicated its involvement in the response against bacterial infections by inducing the release of innate immune mediators.

Therefore, the current results clearly showed a potential defect of granulocytes isolated from Schistosoma-infected patients. It also showed that Th17 cytokines, IL-17 and IL-22, might modulate the response of granulocytes to Schistosoma SEA and not just the recruitment of granulocytes as reported by several studies [52],[53]. In agreement with our results, a previous study reported that Th17 cytokines modulate the inflammatory response of keratinocyte pathways [54].

Previous studies indicated that both cytokines, although secreted from the same cell, might exert differential effects on other cells [52]. S. japonicum products promote Th17 proliferation and differentiation through their effect on granulocyte functions [55].

In conclusion, as observed from the current results, the presence of IL-17 in contrast to IL-22 inhibited the functional activity of granulocytes isolated from either control participants or S. mansoni-infected patients. Therefore, blocking of the IL-17 effect will leave the microenvironment to IL-22 to stimulate the release of granulocytes mediators that will work on the destruction of Schistosoma eggs and the accompanying granuloma. Therefore, anti-IL-17 antibodies may be used as a therapeutic agent for Schistosoma-infected patients.


  Acknowledgements Top


The authors thank the Egyptian Science and Technology Development Fund (STDF) for supporting this study through grant no. 1814 awarded to Dr Soad Nady under the framework of the Egypt/US cooperation program.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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