Introduction: Transforming growth factor β1 (TGF-β1) has a large role in the control of autoimmunity. TGF-β1 production by lymphocytes is reduced in systemic lupus erythematosus (SLE). Decreased levels of TGF-β1 might associate to disease susceptibility, activity and organ damage in SLE. However, the correlation between TGF-β1 levels and severity of renal damage in SLE has not been examined.
Methods: The present study was undertaken to assess the serum levels of total and active TGF-β1 in 150 female patients with SLE and 31 healthy women. Simple and multiple regression analyses between TGF-β1 levels and the diseases-related variables were performed in patients with SLE.
Results: Serum levels of both total and active TGF-β1 were significantly reduced in patients with SLE compared with levels in healthy controls (p < 0.01). Total TGF-β1 levels correlated positively with white blood cell, platelet counts, calculated glomerular filtration rate (GFR), and active TGF-β1 level, and inversely with erythrocyte sedimentation rate (ESR). In multiple regression analysis, ESR and platelet counts remained determinants of total TGF-β1. Total TGF-β1 levels were lower in patients with high disease activity (SLEDAI > 10) and severe organ damage (SLICC > 3). Significantly lower levels of total TGF-β1 were found in patients with severe renal damage, i.e. lower TGF-β1 in patients with 24-h urine protein over 3.5 g than in those with below 3.5 g (p < 0.05); lower TGF-β1 in patients with GFR less than 50 ml/min than in those with over 50 ml/min (p < 0.05). In contrast, active TGF-β1 only correlated with platelet counts. There was no association between renal damage and the levels of active TGF-β1.
Conclusion: This study demonstrates significantly reduced serum levels of both total and active TGF-β1 in women with SLE compared with healthy women. Total TGF-β1 levels are correlated negatively with ESR and positively with blood platelets. Total TGF-β1 levels were lower in SLE patients with high disease activity and severe organ damage. Importantly, the severity of the renal damage was associated with decreased serum levels of total TGF-β1, suggesting that TGF-β1 might be involved in pathogenesis of renal damage caused by lupus nephritis.
ten DijkePHillCS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci2004; 29: 265–273.
2.
LetterioJJRobertsAB. Regulation of immune responses by TGF-beta. Annu Rev Immunol1998; 16: 137–161.
3.
KulkarniABHuhCGBeckerD. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A1993; 90: 770–774.
4.
ShullMMOrmsbyIKierAB. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature1992; 359: 693–699.
5.
YaswenLKulkarniABFredricksonT. Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse. Blood1996; 87: 1439–1445.
6.
GorelikLFlavellRA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity2000; 12: 171–181.
7.
MarieJCLiggittDRudenskyAY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity2006; 25: 441–454.
8.
RazEDudlerJLotzM. Modulation of disease activity in murine systemic lupus erythematosus by cytokine gene delivery. Lupus1995; 4: 286–292.
ChenWJinWCookMWeinerHLWahlSM. Oral delivery of group A streptococcal cell walls augments circulating TGF-beta and suppresses streptococcal cell wall arthritis. J Immunol1998; 161: 6297–6304.
12.
OhtsukaKGrayJDStimmlerMMToroBHorwitzDA. Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol1998; 160: 2539–2545.
13.
Becker-MerokAEilertsenGONossentJC. Levels of transforming growth factor-beta are low in systemic lupus erythematosus patients with active disease. J Rheumatol2010; 37: 2039–2045.
14.
CameronJS. Lupus nephritis. J Am Soc Nephrol1999; 10: 413–424.
15.
DanilaMIPons-EstelGJZhangJVilaLMReveilleJDAlarconGS. Renal damage is the most important predictor of mortality within the damage index: data from LUMINA LXIV, a multiethnic US cohort. Rheumatology (Oxford)2009; 48: 542–545.
16.
AlmehedKForsblad d'EliaHKvistGOhlssonCCarlstenH. Prevalence and risk factors of osteoporosis in female SLE patients-extended report. Rheumatology (Oxford)2007; 46: 1185–1190.
17.
TanEMCohenASFriesJF. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982; 25: 1271–1277.
18.
BombardierCGladmanDDUrowitzMBCaronDChangCH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum1992; 35: 630–640.
19.
GladmanDDUrowitzMBGoldsmithCH. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum1997; 40: 809–813.
20.
CockcroftDWGaultMH. Prediction of creatinine clearance from serum creatinine. Nephron1976; 16: 31–41.
21.
MungerJSHuangXKawakatsuH. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell1999; 96: 319–328.
22.
XingQWangBSuHCuiJLiJ. Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. Rheumatol Int2011; [Epub ahead of print].
23.
KohutEHajduMGergelyP. Expression of TGFbeta1 and its signaling components by peripheral lymphocytes in systemic lupus erythematosus. Pathol Oncol Res2009; 15: 251–256.
24.
JacksonMAhmadYBruceINCoupesBBrenchleyPE. Activation of transforming growth factor-beta1 and early atherosclerosis in systemic lupus erythematosus. Arthritis Res Ther2006; 8: R81–R81.
25.
StaryGKleinIBauerW. Glucocorticosteroids modify Langerhans cells to produce TGF-beta and expand regulatory T cells. J Immunol2011; 186: 103–112.
26.
MarieJCLetterioJJGavinMRudenskyAY. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med2005; 201: 1061–1067.
27.
HugginsMLHuangFPXuDLindopGStottDI. Modulation of autoimmune disease in the MRL-lpr/lpr mouse by IL-2 and TGF-beta1 gene therapy using attenuated Salmonella typhimurium as gene carrier. Lupus1999; 8: 29–38.
28.
WangWHuangXRLiAG. Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7. J Am Soc Nephrol2005; 16: 1371–1383.
29.
HuangXRChungACZhouLWangXJLanHY. Latent TGF-beta1 protects against crescentic glomerulonephritis. J Am Soc Nephrol2008; 19: 233–242.
30.
LiuY. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol2004; 15: 1–12.
YuFWuLHTanY. Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int2010; 77: 820–829.
33.
KoppJBFactorVMMozesM. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest1996; 74: 991–1003.
34.
SaxenaVLieneschDWZhouM. Dual roles of immunoregulatory cytokine TGF-beta in the pathogenesis of autoimmunity-mediated organ damage. J Immunol2008; 180: 1903–1912.
35.
Onetti MudaAFeriozziSRahimiSFaraggianaT. Expression of TGF-beta receptors type I and II in human glomerulonephritis. Nephrol Dial Transplant1998; 13: 279–284.
36.
YamamotoTWatanabeTIkegayaN. Expression of types I, II, and III TGF-beta receptors in human glomerulonephritis. J Am Soc Nephrol1998; 9: 2253–2261.
