Association of interleukin-18 promoter polymorphisms with WHO pathological classes and serum IL-18 levels in Chinese patients with lupus nephritis

Abstract

Accumulating evidence indicates that interleukin (IL)-18 has a central role in the pathogenesis of lupus nephritis (LN). Although two recent studies showed that IL-18 promoter gene polymorphisms might be associated with systemic lupus erythematosus (SLE), to our knowledge, there have not been any reports concerning their association with LN. The aim of our study was to investigate the association of IL-18 promoter polymorphisms with World Health Organization pathological classes and identify their functional correlations. Sequence-specific primer polymerase chain reaction and the restriction fragment length polymorphism method were used to analyse the genotypes of IL-18 promoter polymorphism at the position −607 in 101 unrelated patients with LN, 64 non-renal patients with SLE and 174 ethnically matched healthy controls. Serum IL-18 levels were determined using enzyme-linked immunosorbent assay during the active phase. Immunohistochemical analysis was performed for IL-18 expression on renal biopsies from 72 patients with LN. Our results showed that patients with non-renal SLE had significantly higher frequencies of SNP−607/AA when compared to patients with LN (37.5% vs 18.8%, P < 0.05). LN patients with the AA genotype had significantly lower levels of serum IL-18 than those with the CA or CC genotype (P < 0.01) and also had lower levels of glomerular IL-18 expression than those with the CC genotype (P < 0.05). Significantly, higher frequencies of the SNP−607/AA genotype were observed in LN patients with WHO class III than in those with class IV (34.6% vs 15.6%, P < 0.05). The SNP−607/AA genotype was not observed in patients with LN who progressed to end-stage renal failure that required haemodialysis or renal transplantation. In conclusion, the SNP−607/AA genotype that had lower IL-18 levels might be a genetically protective factor against renal involvement in Chinese patients with SLE and against development of severe nephritis in patients with LN.

Keywords

Chinese interleukin-18 promoter polymorphisms lupus nephritis systemic lupus nephritis

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References

1 Cameron JS Turner DR Ogg CS . Systemic lupus with nephritis: a long-term study. QJM 1979; 48: 1–24.

2 Korbet SM Lewis EJ Schwartz MM . Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 2000; 35: 904–914.

3 Kuroiwa T Lee EG . Cellular interaction in the pathogenesis of lupus nephritis: the role of T cells and macrophages in the amplification of the inflammatory process in the kidney. Lupus 1998; 7: 597–603.

4 Kelley VR Wuthrich RP . Cytokines in the pathogenesis of systemic lupus erythematosus. Semin Nephrol 1999; 19: 57–66.

5 Tokano Y Morimoto S Kaneko H . Levels of IL-12 in the sera of patients with systemic lupus erythematosus (SLE)–relation to Th1- and Th2-derived cytokines. Clin Exp Immunol 1999; 116: 169–173.

6 Akahoshi M Nakashima H Tanaka Y . Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum 1999; 42: 1644–1688.

7 Masutani K Akahoshi M Tsuruya K . Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum 2001; 44: 2097–2106.

8 Okamura H Tsutsi H Komatsu T . Cloning of a new cytokine that induces IFN-γproduction by T cells. Nature 1995; 378: 88–91.

9 Wong CK Ho CY Li EK Lam CWK . Elevation of proinflammatory cytokines (IL-18, IL-17, IL-12) and Th 2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 2000; 9: 589–593.

10.

10 Wong CK Li EK Ho CY Lam CW . Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus. Rheumatology 2000; 39: 1078–1081.

11.

11 Amerio P Frezzolini A Abeni D . Increased IL-18 in patients with systemic lupus erythematosus: relations with Th-1, Th-2, pro-inflammatory cytokines and disease activity. IL-18 is a marker of disease activity but does not correlate with pro-inflammatory cytokines. Clin Exp Rheumatol 2002; 20: 535–538.

12.

12 Wong CK Ho CY Li EK Lam CWK . Elevated production of interleukin-18 is associated with renal disease in patients with systemic lupus erythematosus. Clin Exp Immunol 2002; 130: 345–351.

13.

13 Faust J Menke J Kriegsmann J . Correlation of renal tubular epithelial cell-derived interleukin-18 up-regulation with disease activity in MRL-fas/lpr mice with autoimmune lupus nephritis. Arthritis Rheum 2002; 46: 3083–3095.

14.

14 Calvani N Richard HB Tucci M . Pannarale, Silvestris, F. Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis. Clin Exp Immunol 2004; 138: 171–178.

15.

15 Wilson AG Symons JA McDowell TL McDevitt HO Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997; 94: 3195–3199.

16.

16 Fishman D Faulds G Jeffery R . The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369–1376.

17.

17 Nolan KF Greaves DR Waldmann H . The human interleukin 18 gene maps to 11q22.2-q22.3, closely linked to the DRD2 gene locus and distinct from mapped IDDM loci. Genomics 1998; 51: 161–163.

18.

18 Kalina U Ballas K Koyama N . Genomic organization and regulation of the human interleukin-18 gene. Scand J Immunol 2000; 52: 525–530.

19.

19 Tone M Thompson SA Tone Y Fairchild PJ Waldmann H . Regulation of IL-18 (IFN-gamma-inducing factor) gene expression. J Immunol 1997; 159: 6156–6163.

20.

20 Sugiura T Kawaguchi Y Harigai M . Association between adult-onset Still’s disease and interleukin-18 gene polymorphisms. Genes Immun 2002; 3: 394–399.

21.

21 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: 91–95.

22.

22 Lin YJ Wan L Lee CC . Disease association of the interleukin-18 promoter polymorphisms in Taiwan Chinese systemic lupus erythematosus patients. Genes Immun 2007; 8: 302–307.

23.

23 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: 146–152.

24.

24 Takada T Suzuki E Morohashi K Gejyo F . Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population. Tissue Antigens 2002; 60: 36–42.

25.

25 Hochberg MC . [letter] Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

26.

26 Bombaridier C Gladman DD Urowitz MB Caron D Chang CH . The Committee on Prognosis Studies in SLE. Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 1992; 35: 630–640.

27.

27 Isenberg DA Rahman A Allen E . BILAG 2004: development and initial validation of an updated version of the British Isles Lupus Assessment Group’s disease activity index for patients with systemic lupus erythematosus. Rheumatology (Oxford) 2005; 44: 902–906.

28.

28 Yee CS Farewell V Isenberg DA . British Isles Lupus Assessment Group 2004 index is valid for assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 2007; 56: 4113–4119.

29.

29 Weening JJ D'Agati VD Schwartz MM . The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65: 521–530.

30.

30 Makino H Yamasaki Y Shikata K . Transition of morphologic features in lupus nephritis: does.steroid therapy accelerate glomerulosclerosis. Intern Med 1995; 34: 982–987.

31.

31 Kimura A Sasazuki T . Eleventh International Histocompatibility Workshop reference protocol for the HLA DNA-typing technique. In: K Tsuji M Aizawa T Sasazuki , (eds). HLA. Oxford, New York, Tokyo: Oxford University Press; 1992. p. 397-419.

32.

32 Sivalingarn SP Yoon KH Koh DR Fong KY . Single-nucleotide polymorphism of the interleukin-18 gene promoter region in rheumatoid arthritis patients: protective effect of AA genotype. Tissue Antigens 2003; 62: 498–504.

33.

33 Takeuchi M Okura T Mori T . Intracellular production of interleukin-18 in human epithelial-like cell lines is enhanced by hyperosmotic stress in vitro. Cell Tissue Res 1999; 297: 467–473.

34.

34 Chan RWY Lai FMM Li EKM . Intrarenal cytokine gene expression in lupus nephritis. Ann Rheum Dis 2007; 66: 886–892.

35.

35 Faurschou M Starklint H Halberg P Jacobsen S . Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol 2006; 33: 1563–1569.

36.

36 Tsao BP . Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol 2004; 16: 513–521.

37.

37 Alarcon-Riquelme ME . The genetics of systemic lupus erythematosus: understanding how SNPs confer disease susceptibility. Springer Semin Immunopathol 2006; 28: 109–117.