Up-regulated Complement 3 Production by Toll-like Receptor 9/ Transforming Growth Factor-Beta 1/Complement 3 Pathway in Whole Blood Cells of Lupus Thrombocytopenia

Overview

Journal Arch Rheumatol

Specialty Rheumatology

Date 2018 Jun 15

PMID 29901007

Citations 2

Authors

Yi Yuan

Ling Zhao

Ning Ma

Zhuang Ye

Zhenyu Jiang

Congqiu Chu

Affiliations

Soon will be listed here.

Abstract

Objectives: This study aims to assess the complement 3 (C3) expressions in whole blood cells and verify a pathway toll-like receptor 9 (TLR9)/ transforming growth factor-beta 1 (TGF-β1)/C3 for C3 regulation in mediating thrombocytopenia (TCP) in patients with systemic lupus erythematosus (SLE).

Patients And Methods: The study included 63 newly diagnosed SLE patients (2 males, 61 females; mean age 39.5 years; range 15 to 67 years). Whole blood messenger ribonucleic acid expression for C3, TLR9 and TGF-β1 were measured by quantitative reverse transcription real-time polymerase chain reaction in SLE patients with TCP (n=38) and age- and sex-matched SLE patients without TCP (n=25) at baseline and in 10 SLE patients with TCP after four weeks of treatment. Whole blood cells from SLE patients with TCP were cultured in the presence of TLR9 ligand cytosine-phosphate- guanine, recombinant human TGF-β1, TGF-β receptor inhibitor/activin receptor-like kinase inhibitor SB431542. TGF-β1 and C3 levels in whole blood cells cultures were determined by quantitative reverse transcription real-time polymerase chain reaction and enzyme-linked immunosorbent assay.

Results: Whole blood cells from SLE patients with TCP displayed an enhanced gene expression for C3, TLR9 and TGF-β1 compared with that of SLE patients without TCP (p<0.01 for C3, p<0.05 for TLR9 and TGF-β1). SLE patients with TCP had decreased plasma levels of C3 suggesting excessive consumption. In whole blood cell culture, engagement of TLR9 led to the increased gene expression of C3. Furthermore, TGF-β1 inhibitor abolished TLR9 stimulation on C3 gene expression.

Conclusion: These results suggest that blood cells are the source of extra-hepatic synthesis of C3 in SLE patients with TCP and this synthesis of C3 was up-regulated by TLR9 via induction of TGF-β1. Thus TLR9/TGF-β1/C3 pathway might be in operation mediating lupus thrombocytopenia.

Citing Articles

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications.

Luo J Biomedicines. 2022; 10(5).

PMID: 35625943 PMC: 9138510. DOI: 10.3390/biomedicines10051206.

Microarray-based analysis of renal complement components reveals a therapeutic target for lupus nephritis.

Liu T, Yang M, Xia Y, Jiang C, Li C, Jiang Z Arthritis Res Ther. 2021; 23(1):223.

PMID: 34433493 PMC: 8385907. DOI: 10.1186/s13075-021-02605-9.

References

Hochberg M . Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; 40(9):1725. DOI: 10.1002/art.1780400928. View

Oku K, Atsumi T, Bohgaki M, Amengual O, Kataoka H, Horita T . Complement activation in patients with primary antiphospholipid syndrome. Ann Rheum Dis. 2008; 68(6):1030-5. DOI: 10.1136/ard.2008.090670. View

Qin M, Li Y, Yang X, Wu H . Safety of Toll-like receptor 9 agonists: a systematic review and meta-analysis. Immunopharmacol Immunotoxicol. 2014; 36(4):251-60. DOI: 10.3109/08923973.2013.861481. View

Somerfield S, Roberts M, Booth R . Double-stranded DNA antibodies: a comparison of four methods of detection. J Clin Pathol. 1981; 34(9):1032-5. PMC: 494236. DOI: 10.1136/jcp.34.9.1032. View

Reis E, Barbuto J, Isaac L . Human monocyte-derived dendritic cells are a source of several complement proteins. Inflamm Res. 2006; 55(5):179-84. DOI: 10.1007/s00011-006-0068-y. View

Kayser W, MUELLER-ECKHARDT C, Bhakdi S, Ebert K . Platelet-associated complement C3 in thrombocytopenic states. Br J Haematol. 1983; 54(3):353-63. DOI: 10.1111/j.1365-2141.1983.tb02110.x. View

Polley M, Nachman R . The human complement system in thrombin-mediated platelet function. J Exp Med. 1978; 147(6):1713-26. PMC: 2184322. DOI: 10.1084/jem.147.6.1713. View

Naughton M, Botto M, Carter M, Alexander G, Goldman J, Walport M . Extrahepatic secreted complement C3 contributes to circulating C3 levels in humans. J Immunol. 1996; 156(8):3051-6. View

Falus A . Regulation of complement biosynthesis by tissue-specific and hormonal factors. Immunol Lett. 1990; 24(4):227-30; discussion 231-2. DOI: 10.1016/0165-2478(90)90001-7. View

10.

Lamphier M, Zheng W, Latz E, Spyvee M, Hansen H, Rose J . Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol. 2013; 85(3):429-40. DOI: 10.1124/mol.113.089821. View

11.

Hogasen A, Hestdal K, Hogasen K, Abrahamsen T . Transforming growth factor beta modulates C3 and factor B biosynthesis and complement receptor 3 expression in cultured human monocytes. J Leukoc Biol. 1995; 57(2):287-96. DOI: 10.1002/jlb.57.2.287. View

12.

Ktona E, Barbullushi M, Backa T, Idrizi A, Shpata V, Roshi E . Evaluation of thrombocytopenia in systemic lupus erythematosus and correlation with different organs damages. Mater Sociomed. 2014; 26(2):122-4. PMC: 4035144. DOI: 10.5455/msm.2014.26.122-124. View

13.

Chow E, OConnell R, Schilling S, Wang X, Fu X, Cheng G . TLR agonists regulate PDGF-B production and cell proliferation through TGF-beta/type I IFN crosstalk. EMBO J. 2005; 24(23):4071-81. PMC: 1356307. DOI: 10.1038/sj.emboj.7600867. View

14.

Bombardier C, Gladman D, Urowitz M, Caron D, Chang C . Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992; 35(6):630-40. DOI: 10.1002/art.1780350606. View

15.

Budman D, Steinberg A . Hematologic aspects of systemic lupus erythematosus. Current concepts. Ann Intern Med. 1977; 86(2):220-9. DOI: 10.7326/0003-4819-86-2-220. View

16.

Rokita H, Szuba K . Regulation of acute phase reaction by transforming growth factor beta in cultured murine hepatocytes. Acta Biochim Pol. 1991; 38(2):241-9. View

17.

Falus A, Beuscher H, Auerbach H, Colten H . Constitutive and IL 1-regulated murine complement gene expression is strain and tissue specific. J Immunol. 1987; 138(3):856-60. View

18.

Ghaly N, Kotb N, Nagy H, Rageh E . Toll-like receptor 9 in systemic lupus erythematosus, impact on glucocorticoid treatment. J Dermatolog Treat. 2012; 24(6):411-7. DOI: 10.3109/09546634.2012.697110. View

19.

Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T . TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature. 2010; 465(7300):937-41. PMC: 2964153. DOI: 10.1038/nature09102. View

20.

Haugbro K, Nossent J, Winkler T, Figenschau Y, Rekvig O . Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity. Ann Rheum Dis. 2004; 63(4):386-94. PMC: 1754943. DOI: 10.1136/ard.2003.016303. View