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Rheumatology 2001; 40: 876-881
© 2001 British Society for Rheumatology

Original Papers

Serum interleukin-15 is elevated in systemic lupus erythematosus

M. Aringer1, G. H. Stummvoll1, G. Steiner1, M. Köller1, C. W. Steiner1, E. Höfler2, H. Hiesberger1, J. S. Smolen1,2, and W. B. Graninger1

1 Department of Rheumatology, Internal Medicine III, University of Vienna and
2 Department of Internal Medicine II, Lainz Hospital, Vienna, Austria


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To investigate if interleukin-15 (IL-15) (rather than IL-2) is increased in systemic lupus erythematosus (SLE) and might be responsible for immunological abnormalities of SLE such as the increased lymphocytic expression of Bcl-2 and CD25.

Methods. Serum IL-15, IL-2 and tumour necrosis factor (TNF) levels of 65 SLE patients, 20 healthy persons and 10 rheumatoid arthritis (RA) patients were measured by enzyme-linked immunosorbent assay (ELISA). For 25 SLE patients, the percentage of CD25 + lymphocytes and the lymphocytic Bcl-2 levels were simultaneously determined by fluorocytometry. Peripheral blood mononuclear cells (PBMC) of 15 SLE patients were incubated with or without recombinant IL-15 and the influence on Bcl-2 and CD25 was determined.

Results. IL-15 was found to be elevated in 25 SLE sera (38%), but in none of the 20 healthy sera (P = 0.0005) and none of the 10 RA sera. Both lymphocyte CD25 and Bcl-2 expression significantly correlated with serum IL-15 and were increased by recombinant IL-15.

Conclusion. Serum IL-15 may in part be responsible for the immunological abnormalities seen in active SLE.

KEY WORDS: SLE, IL-15, IL-15R, Lymphocyte, CD25, Bcl-2, IL-2, TNF, ELISA.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
In addition to a variety of autoantibodies [1–3], patients suffering from systemic lupus erythematosus (SLE) show a range of cellular abnormalities, including increased in vitro apoptosis rates, increased apoptosis-related proteins (e.g. Bcl-2), and up-regulated cellular antigens, as well as deranged cytokine production [e.g. of interleukin-2 (IL-2)] [4–7]. Interestingly, elevated IL-2 could indeed explain many of these findings. For example, IL-2 is known to up-regulate the expression of the IL-2 receptor (IL-2R) {alpha}-chain (CD25) [8], and lymphocyte CD25 is up-regulated in active SLE [9, 10]. The same is true for soluble CD25, which is released upon IL-2 stimulation [11] and elevated in SLE sera [12, 13]. As another example, we and others have found that the anti-apoptotic protein Bcl-2 is overexpressed in lupus T lymphocytes [6, 14, 15], an effect which can again be mimicked by in vitro IL-2 stimulation [16].

The data on IL-2 in SLE, however, do not consistently support excessive IL-2 production. On one hand, lupus sera, but not healthy control sera, contain IL-2 [17, 18] and an elevated percentage of unstimulated SLE lymphocytes was found to produce this cytokine [19]. Likewise, increased copies of IL-2 mRNA have been reported, but this finding was not unequivocal [20, 21]. On the other hand, it is known that the in vitro production of IL-2 by human and murine lupus T cells is diminished [22–24], but these findings may rather be due to the inadequate stimulation of lymphocytes [25], which, in turn, may be related to the pre-activation state of SLE lymphocytes [26]. It is therefore not clear at present which of the two sets of findings more closely represents the in vivo situation typical for SLE. Unfortunately, various murine models likewise failed to resolve the dispute [27].

Interestingly, most of the influence attributed to IL-2 could also be exerted by IL-15, given the similarity between IL-15R and IL-2R. IL-15R shares both the IL-2R ß-chain (CD122) and the common {gamma}-chain (CD132) with IL-2R [28, 29]. Thus, the two receptor chains essential for intracellular signal transduction are identical for IL-2R and IL-15R. In consequence, most of the findings that could be due to an influence of IL-2 may likewise be caused by IL-15. Therefore, immune abnormalities of SLE potentially associated with an overexpression of IL-2 could be attributed to IL-15 overproduction. In particular, it has already been demonstrated that IL-15 enhances the expression of the IL-2R {alpha}-chain [30], as well as its release [31], and is also able to induce Bcl-2 expression [32].

We therefore investigated if IL-15 could be responsible for the findings discussed above. It will be shown that serum IL-15 levels are indeed elevated in a considerable proportion of patients with SLE. Moreover, IL-15 levels correlate well with the expression of both the IL-2R {alpha}-chain and the anti-apoptotic protein Bcl-2.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients
Peripheral venous blood was drawn from a random sample of 65 patients (63 Caucasian, one each Hispanic and East-Asian origin; four male; mean age 35 ± 13 yr) fulfilling the American College of Rheumatology (ACR) criteria for SLE [33], 10 Caucasian patients (one male, 60 ± 10 yr) with rheumatoid arthritis [34], and 20 healthy control persons of Caucasian origin (four male, 35 ± 9 yr), all of whom gave their informed consent. The SLE Disease Index Score (SIS) [35], a modified NIH activity index, which correlates very well with all other major lupus activity scores, such as SLEDAI, SLAM, or BILAG [36, 37], was employed to determine the patients’ disease activity. (A SIS of 4 or lower is characteristic of inactive disease, a SIS higher than 12 suggests very active disease.) In addition, the titre of autoantibodies against double-stranded DNA (anti-dsDNA) and, as a measure of complement activation, the C3c values were recorded. At the time of blood drawing, eight patients (12%) suffered from active skin disease, 19 (29%) from florid glomerulonephritis, six (9%) from pleuritis, 16 (25%) from arthritis, and 25 (38%) had lymphopenia or neutropenia. The mean SIS was 5.4 ± 3.5 (mean ± S.D.), the mean daily corticosteroid dosage was 11.4 ± 9.4 mg. Eleven patients (17%) were under cyclophosphamide therapy, nine (14%) on azathioprine, 16 (25%) on anti-malarials, eight (12%) on methotrexate and two (3%) on cyclosporin A.

Enzyme-linked immunosorbent assay (ELISA) for IL-15, IL-2 and tumour necrosis factor (TNF)
Serum samples of SLE patients were tested for IL-15 (n = 65), IL-2 (n = 59), and TNF (n = 40). IL-15 was measured with a commercially available ELISA (R + D Systems, Minneapolis, MN, USA), following the manufacturer's instructions. All values below the detection threshold given by the manufacturer were assigned this value (1 pg/ml). The intra-assay variability was 13.4 ± 10.6% (mean ± S.D.), the inter-assay variability was 16.1 ± 14.9%. Moreover, when spiked serum samples were tested, the recovery rate was 93 ± 8.5%. IL-2 was measured with another commercially available assay (R + D Systems). The detection threshold for this assay was 7 pg/ml. TNF was measured by ELISA (Biosource, Fleurus, Belgium) as described previously [38].

Fluorocytometry
From a random subgroup of patients (n = 25), an additional 10 ml sample of venous blood was anticoagulated with heparin and peripheral blood mononuclear cells (PBMC) were immediately prepared on a Ficoll Paque (Amersham Pharmacia Biotech, Uppsala, Sweden) gradient. Direct immunofluorescence for CD25 was performed under standard conditions using a phycoerythrin (PE)-conjugated anti-CD25 monoclonal antibody or an equally PE-conjugated isotype-matched control antibody (Becton Dickinson, San Jose, CA, USA). Intracellular staining for Bcl-2 was performed [6] employing the FIX + PERM kit (An der Grub, Kaumberg, Austria) and fluorescein isothiocyanate (FITC)-conjugated anti-Bcl-2 monoclonal antibodies or isotype control antibodies (DAKO, Glostrup, Denmark). Fluorocytometry was performed on a Becton Dickinson FACScan flow cytometer as previously described [6].

Stimulation with recombinant human (rh) IL-15
PBMC isolated from heparinized peripheral venous blood from a random group of 15 consecutive SLE patients were resuspended in RPMI medium supplemented with 50% autologous plasma immediately after the final wash. The cells were then incubated at 37°C for 24 h with or without the addition of 10 ng/ml of rhIL-15 (Pharma Biotechnologie, Hannover, Germany). After the incubation, the cells were stained for Bcl-2 or surface stained as above. The cells were counterstained with a combination of FITC- and peridinin chlorophyll protein (PerCP)-conjugated monoclonal antibodies against CD19 and CD3, respectively (Becton Dickinson). The cells were analysed by fluorocytometry, gating for lymphocytes and, in the case of CD25 (PE) surface staining, gating separately for CD3 + or CD19 + lymphocytes, in order to analyse the effects on T and B cells, respectively.

Statistics
The Mann–Whitney test was used for group comparisons in the setting of non-normally distributed groups and Fisher's exact test was used to calculate the differences in categorized data. For testing associations, Spearman rank correlation coefficients were calculated. For normally distributed paired samples, paired t-tests were used. All tests were used two sided. Bonferroni's correction was used where appropriate, and corrected P-values (Pc) < 0.05 were considered significant. Where applicable, values are given as mean ± S.D.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Serum IL-15 is elevated in SLE
The IL-15 levels in healthy control sera were between <=1.00 and 3.76 pg/ml, those in SLE sera were between <=1.00 and 32.64 pg/ml. The distribution of IL-15 did not even remotely follow a Gaussian curve. We therefore defined all values above the 95th percentile of healthy control (3.76 pg/ml) as elevated. As shown in Fig. 1Go, 26 of the 65 SLE patients had elevated serum IL-15 levels [P = 0.0002 (Pc = 0.0004) compared with healthy control; Fisher's exact test]. Interestingly, none of the 10 RA patients had elevated IL-15 levels [P = 0.012 (Pc = 0.025) compared with SLE].



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  		FIG. 1. Serum IL-15 values of individual patients with SLE (filled triangles) as compared with those of healthy controls (open triangles) and patients with RA (filled circles). All values above the shaded area are higher than the 95th percentile of the healthy controls (3.76 pg/ml) and were therefore regarded as elevated.

 

Serum IL-15 correlates with the lymphocyte expression of Bcl-2 and CD25
Based on the known effects of IL-15 on Bcl-2 and CD25 expression, we hypothesized that serum IL-15 might correlate with the expression of both proteins by SLE lymphocytes. To test this hypothesis, we determined the lymphocytic Bcl-2 mean fluorescence intensity (mfi) and the percentage of CD25 + lymphocytes in a random subgroup of 25 consecutive SLE patients and calculated Spearman rank correlation coefficients. Indeed, a significant positive association was found between serum IL-15 and lymphocyte Bcl-2 [r = 0.48, P = 0.019 (Pc = 0.037)] (Fig. 2a) and a borderline association between serum IL-15 and the percentage of CD25 + lymphocytes [r = 0.43, P = 0.043 (Pc = 0.086)] (Fig. 2b).



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  		FIG. 2. Serum IL-15 correlates with lymphocytic Bcl-2 and CD25 expression. Lymphocyte Bcl-2 protein (A) and the percentage of CD25 + lymphocytes (B) of 25 individual SLE patients were correlated with their serum IL-15 levels at the same time point. Spearman rank correlation coefficients were calculated (displayed in the right lower corners). The lines shown derived from Pearson correlation coefficients and are shown for better optical clarity only.

 

IL-15 does not correlate with disease activity
When a possible association between IL-15 and clinical or serological variables was analysed, the only association significant without Bonferroni correction was a negative association between IL-15 and C3c [r = - 0.36, P = 0.006 (Pc = 0.098), data not shown]. No further association with serological or clinical parameters, including dsDNA antibody levels, disease activity as measured by SIS, individual organ involvement, and type or dosage of (immunosuppressive and/or corticosteroid) therapy, was detected (data not shown).

Serum IL-15 does not correlate with serum IL-2 or serum TNF
IL-2 was detectable in six of 59 serum samples from individual SLE patients, but not in any control serum (P = n.s.; Fisher's exact test). IL-2 neither correlated with IL-15, nor with disease activity, Bcl-2, or CD25 + cells. TNF levels were elevated in SLE sera as compared with those of healthy controls (58.85 ± 43.14 vs 15.42 ± 3.98 pg/ml; P < 0.0001). Neither serum IL-15 levels nor lymphocytic Bcl-2 or CD25 correlated with serum TNF. Serum TNF levels did, however, significantly correlate with the disease activity as measured by the SIS [Spearman r = 0.52, P = 0.0013 (Pc = 0.0052)], confirming previous findings [38].

SLE lymphocytes are stimulated by rhIL-15
If the above correlation of IL-15 levels with CD25 and Bcl-2 expression reflected an ongoing in vivo event, such an event should be reproducible in vitro. To this end, using Bcl-2 and CD25 as markers of such an effect, lymphocytes from SLE patients were incubated with or without rhIL-15. IL-15 significantly increased the Bcl-2 contents of SLE lymphocytes [from 326 ± 86 to 381 ± 97 mfi, P < 0.0001 (Pc < 0.0003), paired t-test, Fig. 3a]. IL-15 also increased the percentage of CD25+ lymphocytes both among CD3 + T lymphocytes [35 ± 14 vs 43 ± 15%, P = 0.0002 (Pc = 0.0006), paired t-test, Fig. 3b] and among CD19 + B lymphocytes [27 ± 13 vs 33 ± 13%, P < 0.0001 (Pc < 0.0003), paired t-test, Fig. 3c]. Thus, both T and B lymphocytes of SLE patients are able to respond to IL-15 by up-regulating surface CD25. SLE lymphocytes also respond to IL-15 by increasing their intracellular Bcl-2.



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  		FIG. 3. IL-15 stimulates lymphocytic Bcl-2 and CD25 expression. Lymphocyte Bcl-2 protein (A) and the percentage of CD25 + cells among CD3 + T lymphocytes (B) and among CD19 + B lymphocytes (C) after 24 h of incubation without (left sides) or with rhIL-15 (right- sides) demonstrate a significant effect of IL-15 on SLE lymphocytes. Paired t-tests were calculated (P-values at the top of each panel).

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The data of this study reveal that serum levels of IL-15 are elevated in approximately 40% of patients with SLE. Moreover, IL-15 levels correlate significantly with lymphocytic Bcl-2, while the borderline significance of the association between serum IL-15 and CD25 expression suggests a somewhat stronger influence of other factors. These findings indicate that IL-15 may constitute an alternative stimulus to IL-2 in SLE and may be responsible for some of its immune abnormalities. In fact, in vitro IL-15 enhanced the expression of intracellular Bcl-2 in SLE lymphocytes and of CD25 on their surfaces, proving that SLE lymphocytes can indeed react to IL-15.

Because these experiments were performed in autologous plasma, indirect effects due to a cytokine-mediated rescue of pre-activated cells undergoing apoptosis in starving conditions [39] are unlikely. On the other hand, we have previously found that IL-15 induced Bcl-2 up-regulation in SLE lymphocytes without homologous plasma [32] and can thus exclude the possibility that this effect was mainly mediated by other serum components rather than IL-15.

Theoretically, the observed increase in IL-15 might be due to immunomodulatory drugs. However, neither the type nor the dosage of such medication (or corticosteroids) was associated with serum IL-15, which was therefore most probably associated with the disease itself. Thus, the presented data suggest that IL-15 is increased in SLE, and that this increase may have immunological consequences.

Our present findings do not exclude a similar influence of IL-2 in SLE. However, only 10% of SLE patients had increased IL-2 levels. A cautious view is also supported by the relative paucity of convincing data on an IL-2 excess after two decades of research in this direction. Thus, IL-15 appears to be an attractive alternative stimulus with similar immunological consequences [40–42]. Its possible association with the expression of Bcl-2 is also indirectly supported by another parallel finding: unlike in serum samples of SLE patients, there was no IL-15 excess in RA sera. Similarly, lymphocytes of RA patients do not overexpress Bcl-2 [6, 43]. Thus, IL-15 may at least in part be responsible for the heightened Bcl-2 content of SLE lymphocytes. In addition, the normal IL-15 serum levels of RA patients (in conjunction with the normal distribution of lymphocytic Bcl-2 in RA) indicate that serum IL-15 is not simply a marker of immune activation.

On the other hand, IL-15 was found to be elevated in the synovial fluid of patients with RA, and McInnes and Liew [44] have elegantly argued for a pathogenic role of IL-15 in the synovitic joint microenvironment. Among other findings, they invoke effects of IL-15 on the production of TNF, which is also monocyte/macrophage derived, and on local immunoglobulin production, which is clearly lymphocyte dependent. In contrast to their findings in RA, our data do not suggest a direct relationship between IL-15 and TNF in SLE. As already demonstrated for active SLE [38], TNF levels were elevated in the present patients and significantly associated with their disease activity. TNF did, however, not correlate with IL-15. Nevertheless, like the concentration of IL-15 in SLE sera and RA synovial fluids, the levels of serum TNF in SLE were similar to those found in RA synovial fluids [45].

Another well-known effect of IL-15 that may be of importance in SLE is the stimulatory influence IL-15 exerts on B cells [46]. Excessive antibody production is one of the key features of SLE and hyperactive B cells are a constant feature of human and murine lupus. Both healthy and malignant B cells have been shown to react to IL-15 [47]. In accordance with these data, we find that lupus B lymphocytes react upon IL-15 stimulation by up-regulating CD25.

Taken together, our finding that IL-15 levels are elevated in the sera of patients with SLE and correlate with markers that are potential targets of IL-15 suggests that this cytokine may indeed play a role in the pathogenesis of SLE. Because IL-15 is not directly associated with disease activity, it is not likely to exert such influence as an effector cytokine. IL-15 might rather be involved in tuning the immune system towards autoimmunity. Given that, among blood cells, IL-15 is mainly produced by cells of the macrophage/monocyte cell line [28, 48], but exerts its effects on lymphocytes, IL-15 probably acts in the interface between the activation of monocytes/macrophages and the lymphocyte-dependent effects on autoantibodies and end organs. In this position, IL-15 may prove to impact on the exacerbation and the perpetuation of the disease activity of SLE.


   Notes
 
Correspondence to: J. S. Smolen, Department of Rheumatology, Internal Medicine III, University of Vienna, AKH, Währinger Gürtel 18–20, A-1090 Vienna, Austria Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 1 September 2000; Accepted 5 March 2001


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[Abstract] [Full Text] [PDF]

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