The online version of this article (doi:10.1186/s13075-017-1238-8) contains supplementary material, which is available to authorized users.
Our aim is to study the existence of the TLR9/TGF-β1/PDGF-B pathway in healthy humans and patients with systemic lupus erythematosus (SLE), and to explore its possible involvement in the pathogenesis of lupus nephritis (LN).
Protein levels of the cytokines were detected by ELISA. mRNA levels of the cytokines were analyzed by real-time PCR. MTT assay was used to test the proliferation of mesangial cells under different treatments.
Compared to healthy controls (N Control = 56), levels of Toll-like receptor (TLR)9, transforming growth factor (TGF)-β1, and platelet-derived growth factor B (PDGF-B) were increased significantly in the peripheral blood of SLE patients (N SLE = 112). Significant correlations between the levels of TLR9, TGF-β1, and PDGF-B were observed in both healthy controls and SLE patients. The levels of TGF-β1 and PDGF-B were greatly enhanced by TLR9 activation in primary cell cultures. The proliferation of mesangial cells induced by the plasma of SLE patients was significantly higher than that induced by healthy controls; PDGF-B was involved in this process. The protein levels of PDGF-B homodimer correlated with the levels of urine protein in SLE patients with LN (N LN =38).
The TLR9/TGF-β1/PDGF-B pathway exists in humans and can be excessively activated in SLE patients. High levels of PDGF-B may result in overproliferation of mesangial cells in the kidney that are involved in the development of glomerulonephritis and LN. Further studies are necessary to identify TLR9, TGF-β1, and PDGF-B as new therapeutic targets to prevent the development of glomerulonephritis and LN.
Additional file 1: Table S1. Clinical data of the study subjects. (XLS 23 kb)13075_2017_1238_MOESM1_ESM.xls
Additional file 2: Figure S1. CpG induces upregulation of TGF-β1 and PDGF-B in monocytes in vitro. Isolated monocytes from healthy controls (A and B; N Control = 8) and SLE patients (C and D; N SLE = 7) were stimulated with or without 500 nM CpG for 24 h, and then mRNA expression of TGF-β1 and PDGF-B were detected by qPCR. Multiple rates of mRNA expression of TGF-β1 (E) and PDGF-B (F) in healthy controls (N Control = 8) and SLE patients (N SLE = 7) were calculated as CpG/Media. The results are presented as mean and SEM. (PPTX 510 kb)13075_2017_1238_MOESM2_ESM.pptx
Du X, Poltorak A, Wei Y, Beutler B. Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw. 2000;11:362–71. PubMed
Anders HJ, Vielhauer V, Eis V, Linde Y, Kretzler M, Lema GPD, Strutz F, Bauer S, Rutz M, Wagner H. Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J. 2004;18:534–6. PubMed
Summers SA, Steinmetz OM, Ooi JD, Gan PY, O’Sullivan KM, Visvanathan K, Akira S, Kitching AR, Holdsworth SR. Toll-like receptor 9 enhances nephritogenic immunity and glomerular leukocyte recruitment, exacerbating experimental crescentic glomerulonephritis. Am J Pathol. 2010;177:2234–44. CrossRefPubMedPubMedCentral
Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP, Klotman PE, Thorgeirsson SS. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest. 1996;74:991–1003. PubMed
Floege J, Johnson RJ, Couser WG. Mesangial cells in the pathogenesis of progressive glomerular disease in animal models. Clin Invest. 1992;70:857–64. CrossRef
Papadimitraki ED, Choulaki C, Koutala E, Bertsias G, Tsatsanis C, Gergianaki I, Raptopoulou A, Kritikos HD, Mamalaki C, Sidiropoulos P, Boumpas DT. Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process. Arthritis Rheum. 2006;54:3601–11. CrossRefPubMed
Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64:797–808. CrossRef
Gleeson M, Bishop N, Oliveira M, McCauley T, Tauler P. Sex differences in immune variables and respiratory infection incidence in an athletic population. Exerc Immunol Rev. 2011;17:122–35. PubMed
Thurm CW, Halsey JF. Measurement of cytokine production using whole blood. Curr Protoc Immunol. 2005;Chapter 7(Unit 7):18B.
Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, et al. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol. 2002;62:58–64. CrossRefPubMed
Varga JPB. Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol. 2009;5:7. CrossRef
Sheen YY, Kim MJ, Park SA, Park SY, Nam JS. Targeting the transforming growth factor-beta signaling in cancer therapy. Biomol Ther (Seoul). 2013;21:323–31. CrossRef
Denton CP, Merkel PA, Furst DE, Khanna D, Emery P, Hsu VM, Silliman N, Streisand J, Powell J, Akesson A et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 2007;56(1):323–33.
Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531–7. CrossRefPubMed
- Excessive activation of the TLR9/TGF-β1/PDGF-B pathway in the peripheral blood of patients with systemic lupus erythematosus
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II