Elevated levels of serum IL‑36α in patients with systemic lupus erythematosus

  • Authors:
    • Xue-Rong Wang
    • Jian-Ping Xiao
    • De-Guang Wang
  • View Affiliations

  • Published online on: July 23, 2021     https://doi.org/10.3892/br.2021.1452
  • Article Number: 76
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Abstract

The present study aimed to investigate the levels of IL‑36α and its association with disease activity in patients with systemic lupus erythematosus (SLE). A total of 60 patients with SLE and 29 healthy controls were enrolled in the present study. Disease activity was evaluated using the SLE disease activity index (SLEDAI). The serum levels of IL‑36α, IL‑36 receptor antagonist (IL‑36Ra) and IL‑17 were assessed using ELISA. The levels of IL‑36α in patients with SLE were significantly higher compared with those of healthy controls. There was a significant increase in IL‑36α in the active SLE group (SLEDAI score ≥5) compared with that of the healthy controls (P<0.001). The serum IL‑36α levels were higher in patients with active SLE than in patients with quiescent disease (P=0.012). IL‑36Ra was downregulated in patients with SLE (P=0.007). The serum IL‑17 levels were elevated in patients with SLE (P=0.036), and a positive correlation was observed between the IL‑36α and IL‑17 levels (r=0.453, P=0.003). The serum IL‑36α levels were associated with SLEDAI (r=0.374, P=0.003), proteinuria (r=0.329, P=0.010) and complement 3 (r=‑0.336, P=0.009). Patients who were receiving glucocorticoid treatment had lower IL‑36α levels than those who were not receiving glucocorticoid treatment (P=0.003). Patients with lupus nephritis had higher serum IL‑36α levels compared with those found in patients without lupus nephritis (P=0.037). The serum IL‑36α concentration was elevated in patients with SLE, and was correlated with disease activity and IL‑17 levels. The aberrant serum IL‑36α levels observed in the present study and its clinical association with SLE suggest the important role of IL‑36α in onset and progression of SLE. In addition, the association of IL‑36α with IL‑17 level indicates its involvement in the regulation of T helper 17 cytokines.

Introduction

Members of the IL-1 family of cytokines are key regulators of inflammatory and innate immunity. IL-36 cytokines [including IL-36α, IL-36β, IL-36γ and IL-36 receptor antagonist (IL36Ra)] are members of the IL-1 family (1). IL-36α is particularly expressed in epithelium, keratinocytes, monocytes/macrophages and αβ and γδ T lymphocytes (1). Psoriasis and primary Sjogren's syndrome (pSS) are autoimmune-mediated inflammatory diseases. A previous study showed that IL-36α was involved in the development of psoriasis, it had a pro-inflammatory effect (2). The serum levels of IL-36α were significantly higher in patients with pSS compared with those in subjects complaining of dry mouth or eyes, but who did not meet the American-European Consensus Group criteria for pSS. In addition, the serum levels of IL-36α were correlated with pSS disease activity (3).

Systemic lupus erythematosus (SLE) is also a common autoimmune and inflammatory disease, which is characterized by complement activation, production of numerous auto-antibodies and damage to multiple organs and tissues. A recent study reported the involvement of T helper (Th)17 cells and cytokines in the pathogenesis of SLE (4). Another study demonstrated that plasma IL-17 levels were elevated in patients with new-onset SLE, and a positive correlation was observed between plasma IL-17 and SLE disease activity index (SLEDAI) (5). Yang et al (6) found that IL-17 derived from patients with active SLE could induce the mRNA expression of adhesion molecules, and promoted the recruitment of neutrophils. In addition, IL-36 receptor (IL-36R) signaling appears to be crucial for the control of the IL-23/IL-17/IL-22 axis (7,8). Carrier et al (9) demonstrated that IL-36 cytokines are upregulated by Th17 cytokines, whereas elevated IL-17 expression was observed in psoriasis. IL-36 signaling facilitates the pathogenesis of renal tubulointerstitial lesions through the activation of the NOD-, LRR- and pyrin domain-containing 3 and the IL-23/IL-17 axis (10). Previous studies found that serum IL-36 levels were elevated in patients with SLE (11,12). However, the role of IL-36α in patients with SLE remains to be fully determined. Therefore, the present study investigated the contribution of IL-36α in the development of SLE, and explored the regulatory effect of IL-36α on IL-17 in patients with SLE.

Materials and methods

Study samples

Serum was obtained from patients with SLE (n=60; 55 women and 5 men; median age, 37.5 years, age range, 19-73 years) and healthy controls (n=29; 25 women and 4 men; median age, 32.0 years, age range, 24-45 years) across two centers: The Department of Nephrology of The First and Second Affiliated Hospitals of Anhui Medical University, and the Department of Rheumatology of The Second Hospital of Anhui Medical University). Patients who had suffered various types of malignancy or severe inflammation were excluded from the present study. Healthy controls were selected from the Health Examination Center of The Second Hospital of Anhui Medical University. The diagnosis of SLE cases was based on the American College of Rheumatology 1997 revised criteria for SLE (13). The SLEDAI was used to assess disease activity. A SLEDAI score ≥5 was defined as active SLE, whereas a SLEDAI score <5 was defined as inactive SLE (14). Patients with lupus nephritis were defined by persistent proteinuria (>0.5 g/24 h) or persistent hematuria, presence of cellular casts or renal biopsy supporting (14). All procedures performed in the present study involving human participants were performed in accordance with the Ethical Standards of the Ethics Committee for Human Research at the Second Hospital of Anhui Medical University as well as in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards (15). The present study was approved by the Ethics Committee for Human Research at The Second Hospital of Anhui Medical University (approval no.PJ-YX2017-013), and all the participants provided written informed consent prior to being enrolled in the study.

Biochemical measurements

The patients were made to fast for 8 h after dinner in the night. The fasting blood samples were drawn in the morning, as the blood was also used to measured alanine aminotransferase levels for patients. Blood samples were also collected for determination of albumin, creatinine, complement, immunoglobulin (IgG), erythrocyte sedimentation rate (ESR) and extractable nuclear antigen polypeptide antibodies [antinuclear antibodies, double-stranded (ds)DNA antibodies] all of which were routine examinations. Serum was isolated and stored at -80˚C for measuring IL-36α, IL-36Ra and IL-17 levels. The IL-36α levels (Cusabio Biotech; cat. no. CSB-El011617HU), serum IL-36Ra (Cusabio Biotech; cat. no. CSB-EL011616HU) and IL-17 (R&D Systems, Inc.; cat. no. D1700) levels were measured using human ELISA kits.

Statistical analysis

Data were analyzed using SPSS version 16 (IBM Corp.). The data are presented as the mean ± standard deviation for normally distributed variables, or as the median and interquartile ranges otherwise. Differences between two groups were assessed either by an independent samples Student's t-test or by a Wilcoxon's rank sum test for continuous variables. Correlations between two variables were assessed by Spearman's rank correlation. Two-sided P<0.05 was considered to indicate a statistically significant difference.

Results

In total, 60 patients with SLE, including 47 active patients and 13 inactive patients, and 29 healthy controls were enrolled in the present study. All patients and healthy controls were Chinese. There were no significant differences between patients with SLE and normal controls in terms of age, sex or creatinine levels (Table I). Baseline disease activity (n=60) was highly variable, with SLEDAI scores ranging from 0-36, and a median of 10.58 patients had positive ANA, whereas 30 patients with SLE had positive double-stranded (ds)DNA (Table I). The majority of patients (75%) received prednisone or an equivalent glucocorticoid. In total, 40 patients (66.67%) received glucocorticoids and immunosuppressant (Table I).

Table I

Comparison of clinical and laboratory parameters between the SLE and control group.

Table I

Comparison of clinical and laboratory parameters between the SLE and control group.

VariableSLE group, n=60Control group, n=29P-value
Anti-double stranded DNA, -/+30/30NANA
Antinuclear antibodies, -/+2/58NANA
Albumin, g/l31.40±8.9947.49±2.520.01a
Creatinine, µmol/le66.00 (51.25,117.75)56.00 (50.00,70.50)0.087
Proteinuria, mg/24 he660 (237.5-3062.5)NANA
C3, g/le0.68 (0.44-0.93)NANA
C4, g/le0.09 (0.05-0.22)NANA
IgG, g/le14.75 (11.54-19.45)NANA
IgA, g/le2.48 (1.51-3.28)NANA
IgM, g/le0.95 (0.75-1.35)NANA
Erythrocyte sedimentation rate, mm/he40.00 (22.25-69.25)NANA
SLEDAIe10.00 (6.00-17.50)NANA
Received glucocorticoidsf, n (%)45(75)NANA
Received glucocorticoids or immunosuppressantsg, n (%)40 (66.67)NANA
IL-36α, pg/mle50.08 (39.01-108.02)25.98 (17.19-32.1)0.000c
IL-36Ra, pg/mle42.6 (29.73-107.08)110.45 (45.72-160.95)0.007b
IL-17, pg/mle39.68 (33.03-82.44)35.13 (32.14-41.25)0.036a

[i] aP<0.05;

[ii] bP<0.01;

[iii] cP<0.001;

[iv] dmean ± standard deviation;

[v] emedian (interquartile range);

[vi] fglucocorticoids administered include hydrogenated prednisolone, prednisolone acetate, methylprednisolone;

[vii] gimmunosuppressants administered include Cyclophosphamide, Mycophenolatemofetil and Tacrolimus. NA, not applicable; IL-36Ra, IL-36 receptor antagonist; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index.

The association between serum IL-36α levels with the clinical and laboratory parameters of patients with SLE were analyzed, and the results showed that rash, leukocytes, ESR, anti-dsDNA, proteinuria and hematuresis were positively associated with the serum IL-36α levels in patients with SLE (Table II). A negative correlation was observed between complement 3 and serum IL-36α levels. No significant associations between IL-36α with any other clinical or laboratory parameters were observed (P>0.05; Table II).

Table II

Association between plasma IL-36α levels and clinical and laboratory parameters in the patients with systemic lupus erythematosus.

Table II

Association between plasma IL-36α levels and clinical and laboratory parameters in the patients with systemic lupus erythematosus.

ParametersnSerum IL-36α level, pg/ml, median (interquartile range)P-value
Rash  0.003b
     Yes3669.35 (42.74-141.75) 
     No2441.23 (30.58-59.62) 
Arthritis  0.382
     Yes2253.59 (40.14-140.74) 
     No3849.83 (32.66-95.08) 
Oral ulcer  0.647
     Yes1358.68 (32.70-145.68) 
     No4749.14 (39.11-106.98) 
Nervous system disorder  0.597
     Yes455.96 (21.48-114.11) 
     No5650.08 (39.44-108.02) 
Pleuritis  0.405
     Yes1071.10 (40.10-127.37) 
     No5049.39 (37.95-105.4) 
Pericarditis  0.555
     Yes651.34 (39.60-107.32) 
     No5449.39 (37.95-107.32) 
Lymphopenia  0.007b
     Yes1779.70 (48.73-158.64) 
     No4344.68 (32.72-77) 
Thrombocytopenia  0.085
     Yes24119.61 (58.31-165.61) 
     No3645.12 (32.35-76.09) 
ESR  0.001b
     Yes3377.0 (43.16-150.60) 
     No2742.37 (31.24-49.64) 
Hypocomplementemia  0.025a
     Yes4062.43 (39.59-123.46) 
     No2043.03 (28.48-56.52) 
Anti-double stranded-DNA positive  0.019a
     Yes3058.63 (40.57-150.16) 
     No3043.68 (35.05-75.79) 
Proteinuria  0.037a
     Yes4563.19 (39.66-123.44) 
     No1542.63 (32.72-53.46) 
Hematuresis  0.027a
     Yes2455.40 (39.01-132.48) 
     No3644.34 (36.25-87.91) 
Antinuclear antibodies positive  0.538
     Yes5651.34 (39.59-108.02) 
     No436.28 (31.61-182.15) 

[i] aP<0.05;

[ii] bP<0.01.

Serum IL-36α levels were significantly higher in patients with SLE than in healthy controls [median (interquartile range); 50.08 (39.01-108.02) pg/ml vs. 25.98 (17.19-32.1) pg/ml; P<0.001)], as shown in Fig. 1A. The serum IL-36α levels were significantly higher in the active group compared with those in the inactive group (P=0.012), as shown in Fig. 1B. Serum IL-36Ra levels were significantly lower in patients with SLE than in controls [42.6 (29.73-107.08) pg/ml vs. 110.45 (45.72-160.95) pg/ml, P=0.007)], as shown in Fig. 2A, and it was lower in patients with active SLE compared with the levels found in patients with inactive SLE (P=0.018, Fig. 2B). Serum IL-17 levels were increased in patients with SLE (Fig. 3), but there was no significant difference between patients with active and inactive SLE.

To determine the association between serum IL-36α levels and disease activity, the association between these two parameters was analyzed. A positive correlation between serum IL-36α and the SLEDAI score was observed (r=0.374, P=0.003). In the correlation analysis shown in Fig. 4, the concentration of serum IL-36α was positively correlated with proteinuria (r=0.329, P=0.010).

The present study investigated the association between IL-36α levels with serum IL-17 levels. Serum IL-36α was positively correlated with IL-17 (r=0.453, P=0.003; Fig. 4). Serum IL-36α levels showed an inverse correlation with complement 3 (r=-0.336, P=0.009; Fig. 4). There was no significant correlation between serum IL-36α and IgG, IgA, IgE, IgM, complement 4 or ESR (data not shown).

In total, 45 patients received glucocorticoid treatment, whereas 40 patients with SLE received immunosuppressant and glucocorticoid therapies. Patients (n=45) who had received glucocorticoid treatment had lower IL-36α levels compared with those of patients who had not received glucocorticoid treatment (P=0.003; Fig. 5). These results suggested that immunosuppressant and glucocorticoid therapies may have an inhibitory effect on IL-36α. A total of 47 patients (78.33%) had renal involvement. Patients with nephritis had higher serum IL-36α levels than those without nephritis (P=0.037; Table II). Serum IL-36Ra levels were significantly lower in patients with SLE than in controls. IL-36Ra levels were negatively correlated with SLEDAI (r=-0.360, P=0.001). There was no significant association between IL-36Ra levels and proteinuria, ESR, C3 or C4.

Discussion

A previous study demonstrated that IL-36α binds to a functional heterodimeric receptor complex, which consists of IL-36R, IL-1 receptor (IL-1R)-related protein 2 and IL-1R accessory protein, and activates NF-κB and MAPK to initiate pro-inflammatory pathways (16).

IL-36α is expressed in epithelium and keratinocytes. A previous study indicated that IL-36α may be involved in the pathogenesis of autoimmune disease (2). Previous studies reported that IL-36α exerts pro-inflammatory effects in the skin of patients with psoriasis, who exhibit autoimmune-mediated inflammatory skin lesions (2,17). IL-36 is upregulated in skin lesions caused by psoriasis (18,19). Moreover, transgenic mice overexpressing IL-36α in keratinocytes showed certain similarities to human psoriasis (20).

Although the pathogenesis of SLE is not fully understood, cytokine-mediated immunity plays an important role in SLE (4,5). Currently, little is known regarding the association between IL-36α and SLE. The results of thew present study showed that the serum IL-36α levels were significantly higher in patients with SLE compared with those of the controls, and the serum IL-36α levels were increased in the active SLE group compared with those of the inactive group. Circulating IL-36α levels were correlated with SLEDAI, complement 3 and ESR. These results suggested that IL-36 may be involved in the pathogenesis and progression of SLE.

Studies have shown that glucocorticoids downregulate the serum levels of IL-12 family cytokines and IL-37 (21,22). The most important mechanism by which glucocorticoids exert their anti-inflammatory effects is considered to be the inhibition of the NF-κB activity (21,22). In the present study, patients who were receiving glucocorticoid or immunosuppressant therapy had lower IL-36α levels, indicating that glucocorticoids or immunosuppressants may inhibit the production of IL-36α. Zhang et al (23) found that serum IL-36 levels in patients with SLE did not differ significantly from that of the controls. There are several possible reasons for such inconsistent results. Firstly, the patients in the current study were primarily in the active state. Furthermore, IL-36α rather than all IL-36 cytokines serve an important role in autoimmune diseases (9,24).

A positive correlation between serum IL-36α levels and proteinuria was observed in the present study. Patients with kidney involvement had higher serum IL-36 levels. In agreement with the present study, overexpression of IL-36α (IL-1F6) in the kidney led to increased expression of IL-6, TGF-β receptor-1 and mesenchymal markers, and aggravated tumor-infiltrating lymphocytes in a B6.MRLc1 model (25). In addition, overexpression of IL-36α upregulated α-smooth muscle actin expression. Further studies are required to investigate the expression of IL-36α in lupus nephritis.

IL-17 secretion is primarily derived from Th17 cells, which are CD4+ Th cells that produce IL-17, but not Th1 or Th2 cytokines. Several studies have reported elevated serum IL-17a levels in patients with SLE compared with the levels found in healthy controls (26,27). Although it was not previously reported, the strong correlation between serum IL-36α and IL-17 levels that was found in the present study was expected, since IL-36α acts as a pro-inflammatory cytokine, upregulating pro-inflammatory mediators, such as IL-6, IL-8 and TNF-α, and, in combination with TGF-β, may induce naive T cells to differentiate into Th17 cells (28-31). This observation suggests that IL-36α may affect the Th17 cell response in patients with lupus.

IL-36Ra, which is an endogenous receptor antagonist, displays 50% amino acid sequence homology with IL-1Ra (32). IL-36Ra binds to IL-36R, but does not induce any cellular response. It prevents the interaction of IL-36α, IL-36β and IL-36γ with IL-36R, and thus acts as a endogenous inhibitor (33). In the present study, serum IL-36Ra levels were lower in patients with SLE than in the controls. The results of the present study support the hypothesis that the underlying mechanism of IL-36Ra deficiency leading to the progression of SLE results from the reduced suppressing effect of IL-36Ra on IL-36α responses. This imbalance of IL-36α and IL-36Ra would result in a pathologically increased Th17 response, which is associated with SLE.

The present study recruited 60 patients with SLE and 29 healthy subjects as the control group. This was a relatively small sample size, which may be considered a limitation of the present study. Larger sample sizes are being recruited/collected for more accurate and representative comparisons in future studies.

In conclusion, the present study confirmed that IL-36α was associated with SLE and may be involved in the regulation of Th17 cytokines. Antagonism of IL-36α should be explored as a treatment of SLE. Lower IL-36Ra levels resulted in a reduced inhibitory effect on IL-36α and contributed to SLE development.

Acknowledgements

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Authors' contributions

DGW conceived and designed the study. XRW and JPX performed the experiments and wrote the manuscript. All authors have read and approved the final manuscript. DGW, XRW and JPX confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All procedures performed in the present study involving human participants were performed in accordance with the Ethical Standards of the Ethics Committee for Human Research at the Second Hospital of Anhui Medical University as well as in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The present study was approved by the Ethics Committee for Human Research at The Second Hospital of Anhui Medical University (approval no.PJ-YX2017-013), and all the participants provided written informed consent prior to being enrolled in the study.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Wang X, Xiao J and Wang D: Elevated levels of serum IL‑36α in patients with systemic lupus erythematosus. Biomed Rep 15: 76, 2021
APA
Wang, X., Xiao, J., & Wang, D. (2021). Elevated levels of serum IL‑36α in patients with systemic lupus erythematosus. Biomedical Reports, 15, 76. https://doi.org/10.3892/br.2021.1452
MLA
Wang, X., Xiao, J., Wang, D."Elevated levels of serum IL‑36α in patients with systemic lupus erythematosus". Biomedical Reports 15.3 (2021): 76.
Chicago
Wang, X., Xiao, J., Wang, D."Elevated levels of serum IL‑36α in patients with systemic lupus erythematosus". Biomedical Reports 15, no. 3 (2021): 76. https://doi.org/10.3892/br.2021.1452