Raised expression of cytokine receptor gp130 subunit on peripheral lymphocytes of patients with active lupus. A useful tool for monitoring the disease activity?

Abstract

The glycoprotein gp130 is a signal traducing subunit with a membrane domain of the IL-6 receptor. In addition, gp130 is shared among the receptors for IL-6 superfamily, and it is critically involved in generating signal transduction through these receptors. The aim of the study is to evaluate the expression of the IL-6 superfamily receptor molecule gp130 on TCD4⁺ and B cells in patients with systemic lupus erythematosus (SLE). Surface expression of gp130 on TCD4⁺ and B lymphocytes was higher in patients with SLE than in healthy controls (2.79 vs 0.36% and 8.36 vs 0.37%, respectively). Patients with active lupus had higher expression of gp130 (relapsed 15.1%, new onset 26.6%) than stable patients (2.83%), in B-cell subset, but not in TCD4 lymphocytes. An important reduction in the gp130 expression on B lymphocytes was observed when the activity of the disease had disappeared after readjusting its immunosuppressive treatment (20.8–3.8%). In addition, there was significant correlation between the activity of the disease, measured like systemic lupus erythematosus disease activity index score, and surface expression of gp130 in lymphocytes B (r _s = 0.5880, P = 0.0002). According with our results and roc curve analysis, a cut-off in 6.7% of B cells with gp130 expression were defined, who discriminates active/stable SLE with a sensitivity of 0.93 and a specificity of 0.75. In conclusion, there is an altered expression of gp130 in the patients with SLE. The disease activity as well as immunotherapy seems to influence the pattern of expression of gp130 on B-cell subsets in patients with SLE.

Keywords

gp130 IL-6 lupus monitoring nephritis renal lupus

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References

1 Herrmann M Voll R Kalden JR . Etiopathogenesis of systemic lupus erythematosus. Immunol Today 2000; 21: 424–426.

2 Grammer AC Lipsky PE . B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther 2003; 5: 22–27.

3 Lipsky PE . Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2001; 2: 764–766.

4 Linker-Israeli M Deans RD Wallace DJ Prehn J Ozeri-Chen T Klinenberg JR . Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 1991; 147: 117–123.

5 Llorente L Zou W Levy Y . Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 1995; 181: 839–844.

6 Nagafuchi H Suzuki N Mizushima Y Sakane T . Constitutive expression of IL-6 receptors and their role in the excessive B cell function in patients with systemic lupus erythematosus. J Immunol 1993; 151: 6525–6534.

7 Tesar V Jirsa M Masek Z . Soluble cytokine receptors in renal vasculitis and lupus nephritis. Cas Lek Cesk 1998; 137: 271–275.

8 Herrera-Esparza R Barbosa-Cisneros O Villalobos-Hurtando R Avalos-Diaz E . Renal expression of IL-6 and TNF alpha genes in lupus nephritis. Lupus 1998; 7: 154–158.

9 Horii Y Iwano M Hirata E . Role of interleukin-6 in the progression of mesiangial proliferative glomerulonephritis. Kidney Int Suppl 1993; 39: S71–S75.

10.

10 Kiberd BA . Interleukin-6 receptor blockage ameliorates murine lupus nephritis. J Am Soc Nephrol 1993; 4: 58–61.

11.

11 Pelton BK Hylton W Denman AM . Activation of IL-6 production by UV irradiation of blood mononuclear cells from patients with systemic lupus erythematosus. Clin Exp Immunol 1992; 89: 251–254.

12.

12 Taga T Kishimoto T . Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 1997; 15: 797–819.

13.

13 Hirano T . Interleukin 6 and its receptor: ten years later. Int Rev Immunol 1998; 16: 249–284.

14.

14 Hirano T Matsuda T Nakajima K . Signal transduction through gp-130 is shared among the receptor for the interleukin-6 related cytokine subfamily. Stem Cells 1994; 12: 262–277.

15.

15 McLoughlin RM Jenkins BJ Grail D . IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci U S A. 2005; 102: 9589–9594.

16.

16 Hibi M Murakami M Saito M Hirano T Taga T Kishimoto T . Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 1990; 63: 1149–1157.

17.

17 Tan EM Cohen AS Fries JF . The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.

18.

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

19.

19 Golbus J McCune WJ . Lupus nephritis. Classification, prognosis, immunopathogenesis and treatment. Rheum Dis Clin North Am 1994; 20: 213–242.

20.

20 De La Torre M Alcazar R Urra JM . Monthly cyclophosphamide pulses in the treatment of crescentic glomerulonephritis. Transplant Proc 1998; 30: 3952–3954.

21.

21 Pramanik R Jorgensen TN Xin H Kotzin BL Choubey D . Interleukin-6 induces expression of an interferon-inducible candidate gene for lupus susceptibility. J Biol Chem 2004; 16: 1621–1627.

22.

22 Jacobi AM Odendahl M Reiter K . Correlation between circulating CD27 high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 2003; 48: 1332–1342.

23.

23 Tesar V Masek Z Rychlik I . Cytokines and adhesion molecules in renal vasculitis and lupus nephritis. Nephrol Dial Transplant 1998; 13: 1662–1667.

24.

24 Ripley BJ Goncalves B Isenberg DA Latchman DS Rahman A . Raised levels of interleukin 6 in systemic lupus erythematosus correlate with anaemia. Ann Rheum Dis 2005; 64: 849–853.

25.

25 O’Brien CA Lin SC Bellido T Manolagas SC . Expression levels of gp130 in bone marrow stromal cells determine the magnitude of osteoclastogenic signals generated by IL-6-type cytokines. J Cell Biochem 2000; 1479: 532–541.

26.

26 Lin SCH Yamate T Taguchi Y . Regulation of the gp80 and gp130 subunits of the IL-6 receptor by sex steroids in the murine bone marrow. J Clin Invest 1997; 100: 1980–1990.

27.

27 Narazaki M Yasukawa K Saito T . Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 1993; 82: 1120–1126.

28.

28 Memoli B Grandaliano G Soccio M . In vivo modulation of soluble “antagonistic” IL-6 receptor synthesis and release in ESRD. J Am Soc Nephrol 2005; 16: 1099–1107.

29.

29 Nossent JC Swaak AJG Berden JHM . Systemic lupus erythematosus: analysis of disease activity in 55 patients with end stage renal failure treated with hemodialysis or continous ambulatory peritoneal dialysis. Am J Med 1990; 89: 169–174.

30.

30 Asanuma Y Chunq CP Oeser A . Increased concentration of proatherogenic inflammatory cytokines in systemic lupus erythematosus: relationship to cardiovascular risk factors. J Rheumatol 2006; 33: 445–447.

31.

31 Hirano T Nakajima K Hibi M . Signaling mechanisms through gp130: a model of the cytokine system. Citokine Growth Factor Rev 1997; 8: 241–252.

32.

32 Narimatsu M Maeda H Itoh S . Tissue-specific autoregulation of the stat3 gene and its role in interleukin-6-induced survival signals in T cells. Mol Cell Biol 2001; 21: 6615–6625.

33.

33 Yellin MJ Ulrich Thiene U . T cells in the pathogenesis of systemic lupus erythematosus: potential roles of CD154-CD40 interactions and costimulatory molecules. Curr Rheumatol Rep 2000; 2: 24–31.

34.

34 Bijl M Horst G Limburg P Kallenberg C . Fas expression on peripheral blood lymphocytes in systemic lupus erythematosus (SLE): relation to lymphocyte activation and disease activity. Lupus 2001; 10: 866–872.