Journal List > J Rheum Dis > v.27(2) > 1144379

Lee and Song: Circulating Interleukin-18 Level in Systemic Lupus Erythematosus

Abstract

Objective

This study aimed to evaluate the relationship between circulating interleukin (IL)-18 levels and systemic lupus erythematosus (SLE) and establish a correlation between plasma/serum IL-18 levels and SLE activity.

Methods

We performed a meta-analysis comparing plasma/serum IL-18 levels in patients with SLE to controls by using fixed or random effects model based on the heterogeneity.

Results

Sixteen studies with 659 SLE patients and 502 controls were included in this meta-analysis. Meta-analysis showed that IL-18 levels were significantly higher in the SLE group (standardized mean difference=1.556, 95% confidence interval=1.087∼2.024, p<0.001). Stratifying by ethnicity showed that IL-18 levels were significantly elevated in the SLE groups of European, Asian, and Arab populations. Stratification by adjustment for age and/or sex revealed a significantly higher IL-18 level in the SLE group, independently of the adjustment. Subgroup analysis by sample size showed significantly higher IL-18 levels in the SLE group for both large sample (n≥50) and small sample (n<50) subgroups. Subgroup analysis by data type showed significantly higher IL-18 levels in the SLE group for both original and calculated data populations.

Conclusion

This meta-analysis demonstrated that circulating IL-18 levels are higher in patients with SLE.

REFERENCES

1. Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GR. Systemic lupus erythematosus. Lancet. 2001; 357:1027–32.
crossref
2. Shao WH, Cohen PL. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res Ther. 2011; 13:202.
crossref
3. Nakamura K, Okamura H, Wada M, Nagata K, Tamura T. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun. 1989; 57:590–5.
crossref
4. Nakanishi K. Unique action of interleukin-18 on T cells and other immune cells. Front Immunol. 2018; 9:763.
crossref
5. Amerio P, Frezzolini A, Abeni D, Teofoli P, Girardelli CR, De Pità O, et al. Increased IL-18 in patients with systemic lupus erythematosus: relations with Th-1, Th-2, proinflammatory cytokines and disease activity. IL-18 is a marker of disease activity but does not correlate with proinflammatory cytokines. Clin Exp Rheumatol. 2002; 20:535–8.
6. Sigdel KR, Duan L, Wang Y, Hu W, Wang N, Sun Q, et al. Serum cytokines Th1, Th2, and Th17 expression profiling in active lupus nephritis-IV: from a Southern Chinese Han population. Mediators Inflamm. 2016; 2016; 4927530.
crossref
7. Fouad NA, Baraka EA, Hassan WA. Interleukin-18 gene polymorphisms in systemic lupus erythematosus: relation to disease status. Egypt J Immunol. 2014; 21:1–12.
8. Aghdashi M, Aribi S, Salami S. Serum levels of IL-18 in Iranian females with systemic lupus erythematosus. Med Arch. 2013; 67:237–40.
crossref
9. Koenig KF, Groeschl I, Pesickova SS, Tesar V, Eisenberger U, Trendelenburg M. Serum cytokine profile in patients with active lupus nephritis. Cytokine. 2012; 60:410–6.
crossref
10. Hermansen ML, Hummelshøj L, Lundsgaard D, Hornum L, Keller P, Fleckner J, et al. Increased serum β 2-micro-globulin is associated with clinical and immunological markers of disease activity in systemic lupus erythematosus patients. Lupus. 2012; 21:1098–104.
11. Shimizu C, Fujita T, Fuke Y, Ito K, Satomura A, Matsumoto K, et al. High circulating levels of interleukin-18 binding protein indicate the severity of glomerular involvement in systemic lupus erythematosus. Mod Rheumatol. 2012; 22:73–9.
crossref
12. Sahebari M, Rezaieyazdi Z, Nakhjavani MJ, Hatef M, Mahmoudi M, Akhlaghi S. Correlation between serum concentrations of soluble Fas (CD95/Apo-1) and IL-18 in patients with systemic lupus erythematosus. Rheumatol Int. 2012; 32:601–6.
crossref
13. Xu Q, Tin SK, Sivalingam SP, Thumboo J, Koh DR, Fong KY. Interleukin-18 promoter gene polymorphisms in Chinese patients with systemic lupus erythematosus: association with CC genotype at position-607. Ann Acad Med Singapore. 2007; 36:91–5.
14. Liang D, Ma W, Yao C, Liu H, Chen X. Imbalance of interleukin 18 and interleukin 18 binding protein in patients with lupus nephritis. Cell Mol Immunol. 2006; 3:303–6.
15. Tso TK, Huang WN, Huang HY, Chang CK. Elevation of plasma interleukin-18 concentration is associated with insulin levels in patients with systemic lupus erythematosus. Lupus. 2006; 15:207–12.
16. Lit LC, Wong CK, Tam LS, Li EK, Lam CW. Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus. Ann Rheum Dis. 2006; 65:209–15.
crossref
17. Mosaad YM, Metwally SS, Auf FA, AbdEL-Samee ER, el-Deek B, Limon NI, et al. Proinflammatory cytokines (IL-12 and IL-18) in immune rheumatic diseases: relation with disease activity and autoantibodies production. Egypt J Immunol. 2003; 10:19–26.
18. Liu X, Bao C, Hu D. Elevated interleukin-18 and skewed Th1: Th2 immune response in lupus nephritis. Rheumatol Int. 2012; 32:223–9.
19. Robak E, Woźniacka A, Sysa-Jedrzejowska A, Stepień H, Robak T. Circulating angiogenesis inhibitor endostatin and positive endothelial growth regulators in patients with systemic lupus erythematosus. Lupus. 2002; 11:348–55.
20. Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus. 2000; 9:589–93.
21. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6:e1000097.
crossref
22. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005; 5:13.
crossref
23. Ridout KK, Ridout SJ, Price LH, Sen S, Tyrka AR. Depression and telomere length: a meta-analysis. J Affect Disord. 2016; 191:237–47.
crossref
24. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed.Hillsdale: Lawrence Eribaum Associated;1988.
25. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997; 315:1533–7.
crossref
26. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177–88.
crossref
27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–58.
crossref
28. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629–34.
crossref
29. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000; 56:455–63.
crossref
30. [The levels of plasminogen and inhibitor of plasminogen activators of type 1 in antiphospholipid syndrome]. Ter Arkh. 2012; 84:50–7. Russian.
31. Neumann D, Del Giudice E, Ciaramella A, Boraschi D, Bossù P. Lymphocytes from autoimmune MRL lpr/lpr mice are hyperresponsive to IL-18 and overexpress the IL-18 receptor accessory chain. J Immunol. 2001; 166:3757–62.
crossref
32. Nolan KF, Greaves DR, Waldmann H. The human interleukin 18 gene IL18 maps to 11q22.2-q22.3, closely linked to the DRD2 gene locus and distinct from mapped IDDM loci. Genomics. 1998; 51:161–3.
33. Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol. 2001; 112:146–52.
crossref
34. Song GG, Choi SJ, Ji JD, Lee YH. Association between interleukin-18 polymorphisms and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep. 2013; 40:2581–7.
crossref
35. Lee YH, Nath SK. Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis. Hum Genet. 2005; 118:434–43.
crossref

Figure 1.
Meta-analysis of relationship of interleukin-18 level with systemic lupus erythematosus (SLE). Std diff: standardized difference, CI: confidence interval.
jrd-27-110f1.tif
Figure 2.
Funnel plot investigating the relation of inter-leukin-18 with systemic lupus erythematosus (Egger regression p-value=0.003). Filled circles reflect studies showing publication bias. Diamonds at the bottom of the figure display estimates of summary effect before (open) and after (filled) adjustment of publishing bias. Std diff: standardized difference, Std err: standardized error.
jrd-27-110f2.tif
Table 1.
Characteristics of individual studies included in the meta-analysis
Author Country Ethnicity Cohort size (n) IL-18 levels (pg/mL) Statistical findings
Cases Controls Cases Controls SMD Magnitude* p-value
Sigdel et al., 2016 [6] China Asian 32 24 76.12 11.67 3.291 Large <0.001
Fouad et al., 2014 [7] Egypt Arab 50 50 296.90 112.90 3.504 Large <0.001
Aghdashi et al., 2013 [8] Iran Arab 25 25 281.15 85.12 4.284 Large <0.001
Koenig et al., 2012 [9] Switzerland European 12 14 328.66 67.41 0.894 Large 0.030
Hermansen et al., 2012 [10] Denmark European 26 10 59.00 11.00 1.233 Large 0.002
Shimizu et al., 2012 [11] Japan Asian 12 32 570.00 244.00 2.254 Large <0.001
Sahebari et al., 2012 [12] Iran Arab 114 50 370.28 84.91 0.710 Medium <0.001
Xu et al.-1, 2007 [13] Singapore Asian 48 47 217.30 136.70 0.524 Medium 0.012
Xu et al.-2, 2007 [13] Singapore Asian 22 45 214.20 143.70 0.593 Medium 0.025
Xu et al.-3, 2007 [13] Singapore Asian 6 21 75.30 65.90 0.186 Small 0.688
Liang et al., 2006 [14] China Asian 16 11 767.00 238.90 4.752 Large <0.001
Tso et al., 2006 [15] Taiwan Asian 70 34 254.34 189.66 0.581 Medium 0.006
Lit et al., 2006 [16] Hong Kong Asian 40 40 250.00 171.33 0.805 Large 0.001
Mosaad et al., 2003 [17] Egypt Arab 32 21 2343.46 24.41 1.842 Large <0.001
Liu et al., 2012 [18] China Asian 46 20 146.00 48.00 1.112 Large <0.001
Amerio et al., 2002 [5] Italy European 20 20 278.20 185.00 0.837 Large 0.011
Robak et al., 2002 [19] Poland European 52 20 753.30 267.30 0.864 Large 0.002
Wong et al., 2000 [20] Hong Kong Asian 36 18 368.70 141.10 1.372 Large <0.001

IL-18: interleukin-18, SMD: standard mean difference.

* Magnitude of Cohen's d effect size, where 0.2 to 0.5 is a small effect, 0.5 to 0.8 is a medium effect, and ≥0.8 is a large effect.

Table 2.
Meta-analysis of the association between circulating IL-18 levels and SLE
Groups Population No. of studies Test of association Test of heterogeneity
SMD 95% CI p-value Model p-value I2
All Overall 18 1.556 1.087∼2.024 <0.001 R <0.001 91.0
Ethnicity European 4 0.929 0.596∼1.261 <0.001 F 0.868 0
  Asian 10 1.397 0.828∼1.966 <0.001 R <0.001 88.9
  Arab 4 2.549 0.916∼4.183 0.002 R <0.001 96.5
Adjustment Yes* 11 1.701 1.062∼2.339 <0.001 R <0.001 92.7
  NA 7 0.898 0.663∼1.134 <0.001 R <0.001 86.4
Sample size Number ≥50 12 1.560 0.992∼2.128 <0.001 R <0.001 92.8
  Number <50 6 1.566 0.647∼2.486 0.001 R <0.001 85.6
Data type Original 13 1.652 1.040∼2.264 <0.001 R <0.001 92.1
  Calculated 5 1.343 0.578∼2.108 0.001 R <0.001 88.5

IL-18: interleukin-18, SLE: systemic lupus erythematosus, SMD: standard mean difference, CI: confidence interval, NA: not available, F: fixed effects model, R: random effects model.

* Adjustment or non-significance for age- and/or sex.

Magnitude of Cohen's d effect size (SMD), where 0.2 to 0.5 is a small effect, 0.5 to 0.8 is a medium effect, and ≥0.8 is a large effect.

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