|Year : 2013 | Volume
| Issue : 4 | Page : 123-129
Plasma interleukin-22 and its cellular receptor (IL-22RA1) expression in chronic lymphocytic leukemia
Nihal M. Heiba1, Shereen A. Elshazly2
1 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||30-Apr-2013|
|Date of Acceptance||16-Jul-2013|
|Date of Web Publication||19-Jun-2014|
Nihal M. Heiba
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Ramses St, Abbassia, Cairo 11566
Source of Support: None, Conflict of Interest: None
Chronic lymphocytic leukemia (CLL) is an environment-dependent hematologic malignancy where interactions with accessory cells through cytokines and their receptors seem to confer a survival advantage, thus contributing to disease progression. Interleukin-22 (IL-22) is a T-cell-derived cytokine that promotes cell proliferation and survival through interaction with its receptor IL-22RA1, normally absent in normal immune cells, including B and T lymphocytes.
This study aimed to determine the plasma levels of IL-22 and the expression of IL-22RA1 on malignant cells in patients with B-cell CLL (B-CLL), together with their relation to clinical and prognostic characteristics of the disease.
Patients and methods
The study was carried out on 62 newly diagnosed B-CLL patients. Twenty-five age-matched and sex-matched healthy individuals served as controls. Patients were diagnosed, according to the International Workshop on CLL guidelines, by cytomophology, immunophenotyping, conventional cytogenetic analysis, and fluorescence in-situ hybridization. Plasma IL-22 levels were measured by an enzyme-linked immunosorbent assay and the expression of IL-22RA1 on leukemic cells was assessed by flow cytometry.
Plasma IL-22 was significantly higher in B-CLL patients (range, undetectable 62.9 pg/ml; median, 6.6) compared with control participants (range, undetectable 6.4 pg/ml; median, undetectable) (P<0.01). IL-22RA1 expression was negative in all normal controls, whereas in B-CLL patients it was positively expressed in 35/62 CLL cases (56%). Taking the median level of IL-22RA1 expression in CLL patients as a cutoff level, overexpression (≥10%) was observed in 32/62 (52%) cases. IL-22RA1 expression correlated significantly positively with plasma levels of IL-22 (rs=0.817; P<0.01). Patients presenting with high CD38 expression had significantly higher plasma IL-22 levels compared with those with low CD38 (undetectable 62.9 pg/ml; median, 19.3 vs. undetectable 50.1 pg/ml; median, 3.1) (P<0.01) as well as overexpression of IL-22RA1. No significant relation could be established between either plasma IL-22 levels or IL-22RA1 expression with other clinical features or prognostic criteria of CLL.
This is the first report to describe the aberrant expression of the IL-22 signaling pathway in B-CLL and to link its overexpression with high CD38 expression, a known poor prognostic marker of the disease.
Keywords: chronic lymphocytic leukemia, interleukin-22, IL-22RA1
|How to cite this article:|
Heiba NM, Elshazly SA. Plasma interleukin-22 and its cellular receptor (IL-22RA1) expression in chronic lymphocytic leukemia. Egypt J Haematol 2013;38:123-9
|How to cite this URL:|
Heiba NM, Elshazly SA. Plasma interleukin-22 and its cellular receptor (IL-22RA1) expression in chronic lymphocytic leukemia. Egypt J Haematol [serial online] 2013 [cited 2017 Jun 25];38:123-9. Available from: http://www.ehj.eg.net/text.asp?2013/38/4/123/128298
| Introduction|| |
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by a progressive accumulation of monoclonal B-lymphocytes in the peripheral circulation as well as the lymph nodes and bone marrow (BM), resulting from a deregulation between the proliferation and apoptosis of neoplastic cells 1. In contrast to the in-vivo prolonged survival of B-cell CLL (B-CLL) cells, they constantly undergo rapid and spontaneous apoptosis after a few days of in-vitro culture 2, pointing to the prosurvival influence of microenvironmental factors, particularly the cross-talk between malignant lymphocytes and stromal cells through various cytokines, chemokines, and other soluble factors 3,4. Evidence indicates that T lymphocytes are among those stromal cells that are candidates contributing toward disease progression through the production of several cytokines that can upregulate antiapoptotic proteins and yield survival signals 4–6.
Interleukin-22 (IL-22) is a member of the IL-10 gene family of cytokines that is normally produced by both the adaptive arm of immune system, such as CD4 T-cell subsets, and the innate lymphocytes including natural killer cells and lymphoid tissue inducer-like cells 7,8. It plays an important role in inflammation, including chronic inflammatory diseases and infectious diseases, by exerting multiple effects on the immune system involving acute phase response, activation of the innate immune system, induction of cell migration, inhibition of dendritic cell function, and attenuation of allergic responses 9.
IL-22 is recognized by a heterodimeric receptor complex composed of IL-22RA1 and IL-10R2 10. Although IL-10R2 is ubiquitously expressed, the expression of IL-22RA1 is mainly restricted to epithelial cells, pancreas, small intestine, colon, kidney, and liver, thus providing signaling specificity to tissues 11. Importantly, IL-22RA1 is normally undetectable in immune cells, including monocytes, resting or activated B/T cells, natural killer cells, macrophages, and dendritic cells 12. Binding of IL-22 to this receptor leads to activation of STAT3 signaling cascades and mitogen-activated protein kinase pathways, which are both proliferative and antiapoptotic, allowing for maintenance of epithelial barriers and tissue preservation 13. However, STAT3 and mitogen-activated protein kinase pathways have been reported to be oncogenic, with their constitutive activation being implicated in transformation and progression in many human cancers 14,15. Moreover, it has been reported recently that the IL-22 signaling pathways have biological significance in the pathogenesis of ALK+ anaplastic large cell lymphoma (ALCL) 16 and mantle cell lymphoma (MCL) 17, where IL-22RA1 was found to be expressed in their cell lines and tumors examined.
The clinical relevance of the IL-22 signaling pathway in B-CLL remains largely elusive, and thus far, the levels of IL-22 and its receptor in the disease are ambiguous. Therefore, this study aimed to determine the levels of plasma IL-22 and the expression of its cellular receptor (IL-22RA1) on neoplastic cells by flow cytometry (FCM) in B-CLL, together with their relation to the clinicopathologic characteristics and biological risk factors of the patients at presentation.
| Patients and methods|| |
Sixty-two consecutive newly diagnosed B-CLL patients attending the Hematology/Oncology Unit of Ain Shams University Hospitals, in the period between June 2010 and July 2012, were enrolled in this observational study. There were 43 men and 19 women (M : F, 2.3 : 1) ranging in age from 39 to 82 years (median, 62). Twenty-five age-matched and sex-matched healthy individuals were also included in the study as controls (17 men and eight women; M : F, 2.1 : 1; age range, 35–80 years; median, 60). Exclusion criteria for patients and controls were the presence of active infection, inflammatory diseases, diabetes, or renal diseases. The study was approved by the local ethical committee and an informed written consent was signed by all participants.
Patients were diagnosed in accordance with the guidelines outlined by the International Workshop on CLL 18 after being subjected to full assessment of history, and a thorough clinical and radiological examination. Laboratory investigations, using peripheral blood (PB) and BM aspiration and trephine samples, included the following:
- Complete blood count using Coulter LH 750 (Beckman Coulter Inc., Fullerton, California, USA).
- Microscopic examination of Leishmann-stained PB and BM smears.
- Determination of serum lactate dehydrogenase (LDH) and β2-microglobulin (β2MG) levels.
- Flow cytometric immunophenotyping of lymphocytes (Coulter Epics XL Flow Cytometer; Beckman Coulter Inc.) 19.
- Conventional cytogenetic analysis by the G-banding technique according to standard protocols 20; karyotypes reviewed were interpreted using the International System for Cytogenetic Nomenclature (ISCN) criteria 21.
- Fluorescence in-situ hybridization using probes for the detection of 11q−, 13q−, 17p−, and +12 (Vysis, Downers Grove, Illinois, USA) 22.
Determination of plasma concentration of interleukin-22 by enzyme-linked immunosorbent assay
PB obtained in EDTA anticoagulated evacuated tubes was centrifuged at 1000g for 15 min within 30 min from collection and plasma was separated and kept at −70°C for further analysis using a standard quantitative enzyme immunoassay technique (R&D Systems Inc., Abingdon, UK) according to the manufacturer’s instructions and the end result color change was measured, within 30 min, with a microplate reader set at a wavelength 450 nm and a correction at 540 nm. A standard curve was constructed from which IL-22 concentrations of samples were determined.
Determination of IL-22RA1 expression by flow cytometry
Fresh PB obtained in EDTA anticoagulated evacuated tubes was obtained and processed within 6 h; in cases of unavoidable delay, samples were preserved at room temperature (22–24°C) for a maximum of 24 h. Samples were diluted 1 : 1 with PBS, pH 7.4 (Sigma Chemicals, St Louis, Missouri, USA), the final cell count was adjusted to 5×109–10×109 /ml, and 50 μl was transferred to 5 ml plain tubes for staining with monoclonal antibodies. Cells were Fc-blocked by previous treatment with 1 μg of human IgG/105 cells for 15 min at room temperature; no wash was performed and 10 μl of phycoerythrin-conjugated anti-human IL-22RA1 monoclonal antibodies (R&D Systems Inc.) was added; for control samples, 10 μl of phycoerythrin cyanine 5-labeled anti-CD45 (Beckman Coulter Inc.) was also added, whereas for CLL samples, 10 μl of each phycoerythrin cyanine 5-conjugated anti-CD19 and fluorescein isothiocyanate-conjugated anti-CD5 (Beckman Coulter Inc.) were used. Tubes were incubated for 30–45 min at 2–8°C; cells were then washed in PBS twice, followed by red cell lysis using a 1.5 ml NH4Cl solution buffered with KHCO3 at pH 7.2 for 3 min at room temperature in the dark. After centrifugation, the supernatant was discarded and cells were suspended in PBS. Analysis was carried out using a Coulter Epics XL Flow Cytometer (Coulter Electronics, Hialeah, Florida, USA). For control samples, gating of lymphocytes, monocytes, and granulocytes was performed in a CD45/side-scatter histogram and determination of percentage of cells of different subsets expressing IL-22RA1 was performed relative to isotype-matched controls. For CLL samples, leukemic lymphocytes were gated on the basis of CD5/CD19 coexpression, followed by assessment of the percentage of these neoplastic cells expressing IL-22RA1 relative to isotype-matched controls. [Figure 1] is representative of determination of IL-22RA1 expression by gated CD5/CD19 coexpressing CLL lymphocytes.
|Figure 1: A representative example of the determination of IL-22RA1 expression by B-cell chronic lymphocytic leukemia cells. (a) Lymphocytes were gated in a CD19/side-scatter histogram, (b) malignant B-lymphocytes coexpressing CD5/CD19 were identified, (c) followed by determination of percent of those CD5+/CD19+ cells expressing IL-22RA1. IL-22RA1, interleukin-22 receptor.|
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Continuous data were expressed in the form of range and median and compared using the Mann–Whitney test or the Kruskal–Wallis test as appropriate. Categorical data were expressed as number and percent, and comparisons were made using the χ2-test or Fisher’s exact test as indicated. Correlations between two variables were determined using the Spearman rank correlation coefficient. All tests were two-tailed and a P-value of less than 0.05 was considered statistically significant. For statistical purposes, all IL-22 levels below the detection limit of the assay were considered as equivalent to 2.6 pg/ml. Calculations were carried out using SPSS version 20 (SPSS Inc., Chicago, Illinois, USA) on a Windows 7 operating system.
| Results|| |
Patients’ clinical and hematologic data are presented in [Table 1]. Clinically, they were classified according to the Rai staging system into 10 (16%) presenting in stage 0, 28 (45%) in stages I–II, and 24 (39%) in stages III–IV (advanced disease stages). On the basis of conventional cytogenetic analysis and fluorescence in-situ hybridization data, 22 patients (35%) had either a complex karyotype and/or 11p−, 17p−, or +12 and were allocated to the intermediate-high-risk group, whereas 40 (65%) patients had 13q− or a normal karyotype (which, in this context, indicates the absence of one of the specified abnormalities tested for) and were defined as a favorable risk group 23.
|Table 1: Characteristics of chronic lymphocytic leukemia patients at diagnosis|
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Plasma levels of interleukin-22 in chronic lymphocytic leukemia patients and control participants
Twenty-two of the healthy controls had a plasma IL-22 level below the detection limit of the assay procedure (<2.7 pg/ml). The plasma levels of the entire group ranged from less than 2.7 to 6.4 pg/ml (median, <2.7), being detectable in only 3/25 (12%).
In CLL patients, the plasma IL-22 ranged from less than 2.7 to 62.9 pg/ml (median, 6.6), being significantly higher than the level observed in controls (P<0.01) [Figure 2]a. Twenty-three of 62 CLL patients (37%) had undetectable IL-22 levels compared with 23/25 (88%) control participants (P<0.01) and 32/62 (52%) CLL patients had levels higher than the upper limit of the normal controls. According to the median level recorded in the B-CLL patients (6.6 pg/ml), cases were stratified into a group with high IL-22 (≥6.6 pg/ml), which included 32 patients (52%), and a group with low IL-22 (<6.6 pg/ml), which included 30 patients (48%).
|Figure 2: (a) Plasma interleukin-22 (IL-22) is significantly higher in B-cell chronic lymphocytic leukemia (B-CLL) patients compared with control participants (P<0.01). (b) IL-22RA1 expression by malignant lymphocytes in B-CLL is significantly higher than normal mononuclear cell subsets in control participants (P<0.01). IL-22RA1, interleukin-22 receptor.|
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Expression of IL-22RA1 in chronic lymphocytic leukemia patients and control participants
In all normal PB control samples, mononuclear cells (total) as well as specific subsets of cells (including lymphocytes, monocytes, and granulocytes) were negative for IL-22RA1 relative to the isotype-matched control (<5%). In CLL patients, the percentage of malignant B-lymphocytes expressing IL-22RA1 on their surface ranged from less than 5 to 47% (median, 10), with 27/62 (44%) samples being negative and 35/62 (56%) being positive [Figure 2]b. Taking the median level of IL-22RA1 expression by B-CLL leukemic cells as a cutoff, overexpression (≥10%) was recorded in 32/62 (52%) patients.
Correlation of plasma interleukin-22 levels and IL-22RA1 expression
IL-22RA1 expression by leukemic B-CLL cells correlated significantly positively with the plasma levels of IL-22 (rs=0.817; P<0.01) [Figure 3]. Twenty-six of the 32 patients (81.2%) with high IL-22 levels showed overexpression of IL-22RA1 and 24/31 (80%) with low IL-22 levels had no IL-22RA1 overexpression, whereas of all 62 CLL patients, only 12 (19.4%) had discrepant results (P<0.01).
|Figure 3: IL-22RA1 expression by leukemic B-cell chronic lymphocytic leukemia cells is significantly positively correlated with plasma interleukin-22 (IL-22) levels (r=0.0817; P<0.01). IL-22RA1, interleukin-22 receptor.|
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Relation of plasma interleukin-22 levels and IL-22RA1 expression with the clinical and prognostic characteristics of B-cell chronic lymphocytic leukemia
According to established prognostic factors in CLL; that is, advanced age, male sex, advanced stage at diagnosis (Rai stages III–IV), high serum β2MG levels, high CD38 expression, and intermediate-unfavorable risk cytogenetic group 23, patients were allocated to their respective categories and the levels of plasma IL-22 were assessed in relation to them. Plasma levels of IL-22 were significantly higher in patients with high CD38 expression (range, <2.6–62.9 pg/ml; median, 19.3) compared with those with low CD38 expression (range, <2.6–50.1 pg/ml; median, 3.1) (P<0.01). No statistically significant difference was found in the levels of plasma IL-22 in different disease stages (P>0.05), and there was no significant relation between IL-22 levels and age, sex, serum LDH, and β2MG levels or cytogenetic risk groups (P>0.05) [Table 2]. Grouping of CLL patients according to high and low IL-22 plasma levels yielded the same association of high IL-22 (≥6.6 pg/ml) with high CD38 expression (P<0.01) and no relation with other clinical and prognostic criteria (P>0.05) [Table 3].
|Table 2: Plasma interleukin-22 levels in relation to chronic lymphocytic leukemia clinicopathological characteristics|
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|Table 3: Relation of B-cell chronic lymphocytic leukemia clinical and prognostic criteria with high plasma interleukin-22 and cellular IL-22RA1 overexpression|
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Similarly, overexpression of IL-22RA1 by B-CLL leukemic cells was associated with high CD38 expression (P<0.01), but failed to relate to any other clinical or prognostic feature of the disease (P>0.05) [Table 3].
| Discussion|| |
Accumulation of CD5+/CD19+/CD23+ B-lymphocytes that have escaped programmed cell death and undergone cell cycle arrest in the G0/G1 phase is a hallmark of CLL 24. Recent studies suggest that CLL is a dynamic process that compromises the active generation of subclones with genomic alterations that further alter the birth/death ratios by exploiting microenvironmental interactions with stromal cells through different cytokine and chemokine signals that exert a prosurvival effect and contribute toward disease progression 3,4. IL-22 is known to induce proliferative and antiapoptotic pathways by binding its specific IL-22RA1 receptor 9, albeit little is known about its role in B-CLL; therefore, we decided to explore the levels of IL-22 in the plasma of B-CLL patients together with the expression of its receptor IL-22RA1 on the leukemic lymphocytes by FCM.
Our data documented an elevation in the baseline plasma levels of IL-22 in B-CLL patients compared with control participants. Plasma IL-22 was detectable in 39/62 (63%) patients, in contrast to only 3/25 (12%) controls, with 32/62 (52%) having levels higher than both the upper limit reported in the controls (6.4 pg/ml) and the median of all patients (6.6). The increase in plasma IL-22 seen in B-CLL was more pronounced in patients with high CD38 expression, a marker of poor prognosis. However, other clinical features and prognostic criteria, including age, sex, clinical stage, serum LDH and β2MG levels or cytogenetic-based risk classification, did not influence the levels of IL-22. This was further confirmed when similar results were obtained by comparing patients grouped on the basis of high or low levels of plasma IL-22. Concordant results were reported recently by Gangemi et al. 25.
Knowing that IL-22 is a T-cell-derived cytokine 7, the elevation in plasma IL-22 noted in B-CLL patients could be explained by the accumulating evidence of the ability of malignant lymphocytes to actively attract T cells and alter the T-cell repertoire in order to accumulate them in the microenvironment to modify the local immune response in favor of neoplasm progression 4–6.
The other important and significant finding of the present study is the demonstration of the aberrant expression of the receptor IL-22RA1 on the surface B-CLL leukemic cells by FCM, as it is normally nondetectable in all immune cells, including B and T lymphocytes 12. Although previous data reporting the presence of IL-22RA1 in tumors and cell lines of ALK+ ALCL 16 and MCL 17 exist, to our knowledge, this is the first report of such an expression in B-CLL cases. IL-22RA1 was detectable in 35/62 (56%) CLL patients, with this expression being significantly positively correlated with the plasma levels of IL-22. Overexpression of IL-22RA1 was noted in 32/62 (52%) CLL cases and was significantly associated with high CD38 expression, but not related to other clinical or prognostic characteristics of the disease.
The mechanisms leading to IL-22RA1 expression in malignant B-CLL cells are ambiguous and likely to be variable and/or multifactorial. One possible explanation is that provided by the study of Gelebart et al. 17, who analyzed the gene promoter of IL-22RA1 and found it to contain three consensus binding sequences for nuclear factor-κB (NF-κB), with the pharmacological inhibition of NF-κB resulting in a marked reduction in IL-22RA1 protein expression. As CLL neoplastic cells show higher constitutive activation of NF-κB than normal lymphocytes 26, together with the generally accepted role of NF-κB as one of the most important signal transducers suppressing apoptosis in CLL 27, it could be postulated that NF-κB may contribute toward the aberrant expression of IL-22RA1 observed in some B-CLL cases, especially that NF-κB expression was reported to show individual variations in the disease 28.
Previous studies have described the IL-22-mediated activation of STAT3 in a number of epithelial cells 13,29 as well as ALK+ ALCL 16 and MCL 17, with the resultant enhancement of cell proliferation and survival. In addition, STAT3 phosphorylation was shown to promote the viability of B-CLL cells 30. The concordant detection of IL-22RA1 on B-CLL leukemic cells together with its effector ligand IL-22 in the plasma of patients, described in this work, is a step in providing evidence to support the existence of a functional IL-22 stimulatory pathway that may contribute to the tumorigenicity of the disease through activation of the downstream STAT3 signaling cascades, thus modifying the balance between prosurvival and proapoptotic signals in favor of conferring resistance to apoptosis. Moreover, it is reasonable to postulate that the enhancement in IL-22RA1 expression by NF-κB could be an accessory route through which NF-κB mediates survival and antagonizes apoptosis in addition to its already established mechanisms.
The heterogenic clinical behavior and outcome of CLL is dictated, at least in part, by the nature of microenvironmental signals and interactions existing between stromal cells (as T lymphocytes and other nurse cells) and malignant lymphocytes by cytokines that can promote or impair accumulation of genetic alterations. Existing data have pointed out that an imbalance between cellular molecules and pathways regulating proliferation and apoptosis is observed in poor-prognosis CLL. In this context, several cytokines and receptors are required for the generation, survival, and maintenance of B-CLL cells 3,4.
In this study, patients with higher levels of plasma IL-22 and cellular IL-22RA1 overexpression also presented with high CD38 expression compared with patients with their lower levels. CD38 is accepted as a dependable marker of an unfavorable prognosis and as a functional molecule reflecting the actual state of activation and proliferation of CLL cells.
Leukemic clones with higher numbers if CD38+ cells are characterized by a specific genetic profile that is more responsive to BCR signaling as well as signaling through other cytokine and chemokine receptors. Thus, CD38 expression by cells provides a more global molecular bridge to the environment, rendering signal transduction, chemotaxis, and homing more efficient and favoring survival/proliferation pathways 31.
As the IL-22 signaling pathway might play a role in the progression of B-CLL through induction of an antiapoptotic process, and as CD38 is considered as a dynamic ‘real-time’ indicator of the level of leukemic proliferation, capable of determining the clinical course and outcome of an individual patient, and ultimately influenced by stimulation through cell surface receptors for antigens and cytokines within the microenvironment 31, it is possible to speculate that high plasma IL-22 levels and IL-22 overexpression coupled with high CD38 expression act in synergy to activate genetic programs relevant for proliferative responses and inhibition of apoptosis, playing a role in the poor prognosis in B-CLL patients 25. Of note, we could not fully assess the prognostic impact and effect on response to therapy of the IL-22 signaling pathway expression because of the relatively short time duration of the study compared with the prolonged progression free periods recorded in the disease together with the difficulty in the achievement of complete remission 32; larger scale investigations with long follow-up periods are needed for accurate evaluation of such an impact.
| Conclusion|| |
The present work is the first to describe the aberrant expression of the IL-22 signaling pathway in B-CLL patients, where the increased levels of plasma IL-22 correlated with the expression of its receptor IL-22RA1 on leukemic lymphocytes. Furthermore, baseline higher levels of plasma IL-22 and IL-22 overexpression were associated with high CD38 expression, a dependable marker of poor prognosis. Further studies are warranted to unveil the biological importance of this pathway in the pathophysiology of the disease as well as to investigate its possible use as a marker of an unfavorable prognosis and whether its inhibition could have any therapeutic implications in the treatment of the disease.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]