Extracellular signal–regulated kinase 1/2 signalling in SLE T cells is influenced by oestrogen and disease activity

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs primarily in women of reproductive age. The disease is characterized by exaggerated T-cell activity and abnormal T-cell signalling. The mitogen-activated protein kinase (MAPK) pathway is involved in the maintenance of T-cell tolerance that fails in patients with SLE. Oestrogen is a female sex hormone that binds to nuclear receptors and alters the rate of gene transcription. Oestrogen can also act through the plasma membrane and rapidly stimulate second messengers including calcium flux and kinase activation. In this study, we investigated whether oestrogen influences the activation of MAPK signalling through the phosphorylation of extracellular signal–regulated kinase 1/2 (ERK1/2) in activated SLE T cells. SLE and control T cells were cultured in serum-free medium without and with oestradiol (10⁻⁷ M) for 18 h. The T cells were activated with phorbol 12 myristate 13-acetate and ionomycin for various time points (0–60 min), and the amount of phosphorylated ERK1/2 was measured by immunoblotting. There were no differences in ERK1/2 phosphorylation between SLE and control T cells at 5 and 15 min after the activation stimulus. However, comparison between the amount of phosphorylated ERK1/2 in SLE T cells from the same patients cultured without and with oestradiol showed a significant oestrogen-dependent suppression (P = 0.48) of ERK1/2 in patients with inactive/mild systemic lupus erythematosus disease activity index (SLEDAI) (0–2) compared with patients with moderate (4–6) or active (8–12) SLEDAI scores. These results suggest that the suppression of MAPK through ERK1/2 phosphorylation is sensitive to oestradiol in patients with inactive or mild disease, but the sensitivity is not maintained when disease activity increases. Furthermore, studies are now necessary to understand the mechanisms by which oestrogen influences MAPK activation in SLE T cells.

Keywords

ERK 1/2 activation MAPK signalling oestrogen SLE T cell

Get full access to this article

View all access options for this article.

References

1 Manson JJ Rahman A . Systemic lupus erythematosus. Orphanet J Rare Dis 2006; 1: 1–6.

2 Nagy G Konez A Philips PE Perl A . Mitochondrial signal transduction abnormalities in systemic lupus erythematosus. Curr Immunol Rev 2005; 1: 61–67.

3 Tucker LB Menon S Schaller JG Isenberg DA . Adult and childhood-onset systemic lupus erythematosus: a comparison of onset, clinical and immunological characteristics. Ann Rheum Dis 1995; 50: 702–705.

4 Tsokos GC . Immune cell signaling and gene transcription in human lupus: the time has come. Int Rev Immunol 2004; 23: 221–224.

5 Kyttaris VC Tsokos GC . T lymphocytes in systemic lupus erythematosus: an update. Curr Opin Rheumatol 2004; 16: 548–552.

6 Csiszar A Nagy G Gergely P Pozsonyi T Pocsik E . Increased interferon-gamma (IFN-γ), IL-10 and decreased IL-4 mRNA expression in peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 2000; 122: 464–470.

7 Rider V Jones SR Evans M Abdou NI . Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells. Clin Immunol 2000; 96: 124–134.

8 Rider V Abdou NI . Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus. Int Immunopharmacol 2001; 1: 1009–1024.

9 Li X Rider V Kimler BF Abdou NI . Estrogen does not regulate CD154 mRNA stability in systemic lupus erythematosus T cells. Lupus 2006; 15: 1–6.

10.

10 Franklin RA Tordai A Patel H Gardner AM Johnson GL Gelfand EW . Ligation of the T cell receptor complex results in activation of the Ras/Raf-1/MEK/MAPK cascade in human T lymphocytes. J Clin Invest 1994; 93: 2134–2140.

11.

11 Yi Y McNerney M Datta SK . Regulatory defects in Cbl and mitogen-activated protein kinase (Extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. J Immunol 2000; 165: 6627–6634.

12.

12 Cedeno S Cifarelli D Blasini A . Defective activity of ERK-1 and ERK-2 mitogen-activated protein kinases in peripheral blood T lymphocytes from patients with systemic lupus erythematosus: potential role of altered coupling of Ras guanine nucleotide exchange factor hSos to adapter protein Grb2 in lupus T cells. Clin Immunol 2003; 106: 41–49.

13.

13 Deng C Kaplan MJ Yang J . Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum 2001; 44: 397–407.

14.

14 Oelke K Richardson B . Decreased T cell ERK pathway signaling may contribute to the development of lupus through effects on DNA methylation and gene expression. Int Rev Immunol 2004; 23: 315–331.

15.

15 Tsai MJ O’Malley BW . Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 1994; 63: 451–486.

16.

16 Pedram A Razandi M Levin ER . Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol 2006; 20: 1996–2009.

17.

17 Boonyaratanakornkit V Edwards DP . Receptor mechanisms mediating non-genomic actions of sex steroids. Semin Reprod Med 2007; 25: 139–153.

18.

18 Migliaccio A Pagano M Auricchio F . Immediate and transient stimulation of protein tyrosine phosphorylation by estradiol in MCF-7 cells. Oncogene 1993; 8: 2183–2191.

19.

19 Chen DB Bird IM Zheng J Magness RR . Membrane estrogen receptor dependent extracellular signal-regulated kinase pathway mediates acute activation of endothelial nitric oxide synthase by estrogen in uterine artery endothelial cells. Endocrinology 2004; 145: 113–125.

20.

20 Endoh H Sasaki H Maruyama K . Rapid activation of MAP kinase by estrogen in the bone cells line. Biochem Biophys Res Commun 1997; 235: 99–102.

21.

21 Marques DC Pietras FJ . Membrane-associated binding sites for estrogen contribute to growth regulation of human breast cancer cells. Oncogene 2001; 20: 5420–5430.

22.

22 Kousteni S Chen JR Bellido T . Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 2002; 298: 843–846.

23.

23 Garmy-Susini B Delmas E Gourday P . Role of fibroblast growth factor-2 isoforms in the effect of estradiol on endothelial cell migration and proliferation. Circ Res 2004; 94: 1301–1309.

24.

24 Rider V Li X Peterson G Dawson J Kimler BF Abdou NI . Differential expression of estrogen receptors in women with systemic lupus erythematosus. J Rheumatol 2006; 33: 1093–1101.

25.

25 Kassi E Vlachoyiannopoulos PG Kominakis A Kiaris H Moutsopoulos HM Moutsatsou P . Estrogen receptor alpha gene polymorphism and systemic lupus erythematosus: a possible risk? Lupus 2005; 14: 391–398.

26.

26 Rider V Jones S Evans M Bassiri H Afsar Z Abdou NI . Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. J Rheumatol 2001; 28: 2644–2649.

27.

27 Straub RH . The complex role of estrogens in inflammation. Endocr Rev 2007; 28: 521–574.

28.

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

29.

29 Rappoport MJ Mor A Amit M . Decreased expression of the p21Ras stimulatory factor hSos in PBMC from inactive SLE patients. Lupus 1999; 8: 24–28.

30.

30 Song RXD Mcpherson RA Adam L . Linkage of rapid estrogen action to MAPK activation by ERα-Shc association and Shc pathway activation. Mol Endocrinol 2002; 16: 116–127.

31.

31 Santen RJ Song RX Zhang Z Yue W Kumar R . Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer. Clin Cancer Res 2004; 10: 337s–345s.

32.

32 Belcher SM Le HH Spurling L Wong JK . Rapid estrogenic regulation of extracellular signal-regulated kinase 1/2 signaling in cerebellar granule cells involves a G protein-and protein kinase A-dependent mechanism and intracellular activation of protein phosphatase 2A. Endocrinology 2005; 146: 5397–5406.

33.

33 Kammer GM Laxminarayan D Khan IU . Mechanisms of deficient type I protein kinase A activity in lupus T lymphocytes. Int Rev Immunol 2004; 23: 225–244.

34.

34 Suzuki T Shimizu T Yu H-P . 17-β estradiol administration following trauma-hemorrhage prevents the increase in Kupffer cell cytokine production and MAPK activation predominately via estrogen receptor-α. Surgery 2006; 140: 141–148.

35.

35 Li W Whaley C Mondino A Mueller D . Blocked signal transduction to the ERK and JNK protein kinases in anergic CD+ T cells. Science 1996; 271: 1276–1278.

36.

36 Kammer GM Perl A Richardson BC Tsokos GC . Abnormal T cell signal transduction in systemic lupus erythematosus. Arthritis Rheum 2002; 46: 1139–1154.

37.

37 Whitehurst CE Boulton TG Cobb MH Geppert TD . Extracellular signal–regulated kinases in T cells. Anti-CD3 and 4 beta-phorbol 12-myristate 13-acetate-induced phosphorylation and activation. J Immunol 1992; 148: 3230–3237.