Skip to main content

Advertisement

SpringerLink
Log in

Upregulated expression of STAT3/IL-17 in patients with systemic lupus erythematosus

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Elevated IL-17 levels with higher Th17 numbers are identified in systemic lupus erythematosus (SLE). STAT3 signaling plays a crucial role in the Th17 generation, and SOCS3 negatively regulates their formation. We investigated IL-17, STAT3, and SOCS3 expression, and analyzed their correlations to elucidate the regulatory mechanisms of IL-17 production in SLE. This study enrolled 32 patients, and venous mononuclear cells (MNCs) were isolated with further purification of CD4-positive T cells. IL-17 and SOCS3 levels were measured by real-time quantitative PCR, and pSTAT3/STAT3 expression was analyzed by immunoblot. Elevated IL-17 and SOCS3 levels were identified in lupus patients. There were higher IL-17 levels in lupus nephritis (class IV) than in SLE without renal involvement. Positive correlations were found between IL-17 levels and SOCS3 expression, lupus activity (SLEDAI-2K), or daily proteinuria. There were higher intensities of pSTAT3/β-actin and STAT3/β-actin in SLE, and a positive correlation between IL-17 expression and pSTAT3/β-actin or STAT3/β-actin intensity. Lupus nephritis (class IV) had higher STAT3/β-actin intensity than SLE without renal involvement. These results suggest upregulated STAT3/IL-17 expression in lupus patients. Such findings might facilitate the development of novel compounds and the application of existing therapeutics targeting the STAT3/IL-17 signal in SLE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Katsuyama T, Tsokos GC, Moulton VR (2018) Aberrant T cell signaling and subsets in systemic lupus erythematosus. Front Immunol 9:1088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shuai K, Liu B (2003) Regulation of JAK-STAT signaling in the immune system. Nat Rev Immunol 3(11):900–911

    Article  CAS  PubMed  Google Scholar 

  3. Yin Y, Liu W, Dai Y (2015) SOCS3 and its role in associated diseases. Hum Immunol 76(10):775–780

    Article  CAS  PubMed  Google Scholar 

  4. Liang Y, Xu WD, Peng H, Pan HF, Ye DQ (2014) SOCS signaling in autoimmune diseases: molecular mechanisms and therapeutic implications. Eur J Immunol 44(5):1265–1275

    Article  CAS  PubMed  Google Scholar 

  5. Sukka-Ganesh B, Larkin J III (2016) Therapeutic potential for targeting the suppressor of cytokine signalling-1 pathway for the treatment of SLE. Scand J Immunol 84(5):299–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A 103(21):8137–8142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452(7188):773–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725

    Article  CAS  PubMed  Google Scholar 

  9. Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29(2):288–291

    PubMed  Google Scholar 

  10. Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR (1991) Lupus erythematosus in the 1980s: a survey of 570 patients. Semin Arthritis Rheum 21(1):55–64

    Article  CAS  PubMed  Google Scholar 

  11. Wang CR, Liu MF (2003) Regulation of CCR5 expression and MIP-1α production in CD4+ T cells from patients with rheumatoid arthritis. Clin Exp Immunol 132(2):371–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Peng JS, Chen SY, Wu CL, Chong HE, Ding YC, Shiau AL, Wang CR (2016) Amelioration of experimental autoimmune arthritis through targeting synovial fibroblasts by the intra-articular delivery of microRNA-140-3p and -5p. Arthritis Rheumatol 68(2):370–381

    Article  CAS  PubMed  Google Scholar 

  13. Krebs CF, Panzer U (2018) Plasticity and heterogeneity of Th17 in immune-mediated kidney diseases. J Autoimmun 87:61–68

    Article  CAS  PubMed  Google Scholar 

  14. Liu MF, Wang CR (2014) Increased Th17 in flow cytometer-sorted CD45RO-positive memory CD4 T cells from patients with systemic lupus erythematosus. Lupus Sci Med 1(1):e000062

    Article  PubMed  PubMed Central  Google Scholar 

  15. Raychaudhuri SK, Saxena A, Raychaudhuri SP (2015) Role of IL-17 in the pathogenesis of psoriatic arthritis and axial spondyloarthritis. Clin Rheumatol 34(6):1019–1023

    Article  PubMed  Google Scholar 

  16. Satoh Y, Nakano K, Yoshinari H, Nakayamada S, Iwata S, Kubo S, Miyagawa I, Yoshikawa M, Miyazaki Y, Saito K, Tanaka Y (2018) A case of refractory lupus nephritis complicated by psoriasis vulgaris that was controlled with secukinumab. Lupus 27(7):1202–1206

    Article  CAS  PubMed  Google Scholar 

  17. O'She JJ, Holland SM, Staudt LM (2013) Mechanisms of JAK/STAT signaling in immunity and disease. N Engl J Med 368(2):161–170

    Article  CAS  Google Scholar 

  18. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC (2007) Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity 40(1):1–8

    Article  CAS  PubMed  Google Scholar 

  19. Hedrich CM, Rauen T, Apostolidis SA, Grammatikos AP, Rodriguez Rodriguez N, Ioannidis C, Kyttaris VC, Crispin JC, Tsokos GC (2014) Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc Natl Acad Sci U S A 111(37):13457–13462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Edwards LJ, Mizui M, Kyttaris V (2015) Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice. Clin Immunol 158(2):221–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang X, Guo Y, Bao C, Shen N (2011) Multidimensional single cell based STAT phosphorylation profiling identifies a novel biosignature for evaluation of systemic lupus erythematosus activity. PLoS One 6(7):e21671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Goropevšek A, Holcar M, Avčin T (2017) The role of STAT signaling pathways in the pathogenesis of systemic lupus erythematosus. Clin Rev Allergy Immunol 52(2):164–181

    Article  CAS  PubMed  Google Scholar 

  23. Chikuma S, Kanamori M, Mise-Omata S, Yoshimura A (2017) Suppressors of cytokine signaling: potential immune checkpoint molecules for cancer immunotherapy. Cancer Sci 108(4):574–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu K, Liang C, Liang Z, Tus K, Wakeland EK (2005) Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes. J Immunol 174(3):1630–1637

    Article  CAS  PubMed  Google Scholar 

  25. Isomäki P, Alanärä T, Isohanni P, Lagerstedt A, Korpela M, Moilanen T, Visakorpi T, Silvennoinen O (2007) The expression of SOCS is altered in rheumatoid arthritis. Rheumatology 46(10):1538–1546

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are indebted to the doctors and nurses involved in the diagnosis and management of reported patients at the National Cheng Kung University Hospital.

Funding

This work was supported by grants MOST 106-2314-B-006-073-MY3 and 106-2320-B-006-074 from the Ministry of Science and Technology, Taiwan.

Author information

Authors and Affiliations

  1. Section of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan

    Shih-Yao Chen, Ming-Fei Liu & Chrong-Reen Wang

  2. Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan

    Pin-Yu Kuo & Chrong-Reen Wang

Authors
  1. Shih-Yao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-Fei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pin-Yu Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chrong-Reen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Author contributions are as follows. MFL created the concept. CRW designed the study. SYC and PYK performed the experiments. SYC, MFL, and CRW analyzed the data. CRW wrote the manuscript.

Corresponding author

Correspondence to Chrong-Reen Wang.

Ethics declarations

Disclosures

None.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, SY., Liu, MF., Kuo, PY. et al. Upregulated expression of STAT3/IL-17 in patients with systemic lupus erythematosus. Clin Rheumatol 38, 1361–1366 (2019). https://doi.org/10.1007/s10067-019-04467-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-019-04467-8

Keywords

Search

Navigation