SpringerLink
Log in

Increased expression of long noncoding RNAs LOC100652951 and LOC100506036 in T cells from patients with rheumatoid arthritis facilitates the inflammatory responses

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The aim of this study was to evaluate whether the presence of aberrantly expressed lncRNAs could promote T cell inflammatory responses in patients with RA. The expression levels of 10 potential aberrantly expressed lncRNAs were evaluated in T cells from 39 patients with RA and 17 controls using real-time reverse transcription polymerase chain reaction. The aberrantly expressed lncRNAs were measured in Jurkat cells co-cultured with or without ionomycin and phorbol 12-myristate 13-acetate. Transfection studies using small interfering RNA (siRNA) were conducted for biological functions, and microarray analysis was performed to search for target genes of specific lncRNAs. We confirmed that the expression levels of LOC100652951 and LOC100506036 were higher in RA T cells compared with controls. RA patients treated with biologic agents had lower expression levels of LOC100652951, and female RA patients had lower LOC100506036 expression levels after multivariate analysis. After activation, the expression levels of LOC100506036, but not LOC100652951, increased in Jurkat cells. Transfection of siRNA targeting LOC100506036 inhibited interferon gamma production and the expression of nuclear factor of activated T cells in activated Jurkat cells. After the microarray analysis with validation, inhibition of LOC100506036 expression by siRNA leaded to the decreased expression of sphingomyelin phosphodiesterase 1 (SMPD1). In conclusion, the expression levels of LOC100652951 and LOC100506036 were increased in RA T cells. Treatment with biologic agents could lower the expression of LOC100652951 in RA T cells. LOC100506036 could regulate the expression of SMPD1 and NFAT1 and could contribute to the inflammatory responses in RA.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ACPA:

Anti-citrullinated protein antibody

CRP:

C-reactive protein

ELISA:

Enzyme-linked immunosorbent assay

IFN-γ:

Interferon gamma

lncRNAs:

Long noncoding RNAs

MW:

Molecular weight

ncRNAs:

Noncoding RNAs

PBMCs:

Peripheral blood mononuclear cells

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

RT-PCR:

Reverse transcription polymerase chain reaction

SD:

Standard deviation

siRNA:

Small interfering RNA

SMPD1:

Sphingomyelin phosphodiesterase 1

TNF:

Tumor necrosis factor

References

  1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–19.

    Article  CAS  PubMed  Google Scholar 

  2. Cooles FA, Isaacs JD. Pathophysiology of rheumatoid arthritis. Curr Opin Rheumatol. 2011;23:233–40.

    Article  CAS  PubMed  Google Scholar 

  3. Kobezda T, Ghassemi-Nejad S, Mikecz K, Glant TT, Szekanecz Z. Of mice and men: how animal models advance our understanding of T-cell function in RA. Nat Rev Rheumatol. 2014;10:160–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gizinski AM, Fox DA. T cell subsets and their role in the pathogenesis of rheumatic disease. Curr Opin Rheumatol. 2014;26:204–10.

    Article  CAS  PubMed  Google Scholar 

  5. Weyand CM, Yang Z, Goronzy JJ. T-cell aging in rheumatoid arthritis. Curr Opin Rheumatol. 2014;26:93–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349:1907–15.

    Article  CAS  PubMed  Google Scholar 

  7. Fitzgerald KA, Caffrey DR. Long noncoding RNAs in innate and adaptive immunity. Curr Opin Immunol. 2014;26:140–6.

    Article  CAS  PubMed  Google Scholar 

  8. Heward JA, Lindsay MA. Long non-coding RNAs in the regulation of the immune response. Trends Immunol. 2014;35:408–19.

    Article  CAS  PubMed  Google Scholar 

  9. Hrdlickova B, Kumar V, Kanduri K, Zhernakova DV, Tripathi S, Karjalainen J, et al. Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity. Genome Med. 2014;6:88.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Stuhlmüller B, Kunisch E, Franz J, Martinez-Gamboa L, Hernandez MM, Pruss A, et al. Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue. Am J Pathol. 2003;163:901–11.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Müller N, Döring F, Klapper M, Neumann K, Schulte DM, Türk K, et al. Interleukin-6 and tumour necrosis factor-alpha differentially regulate lincRNA transcripts in cells of the innate immune system in vivo in human subjects with rheumatoid arthritis. Cytokine. 2014;68:65–8.

    Article  PubMed  Google Scholar 

  12. Song J, Kim D, Han J, Kim Y, Lee M, ** EJ. PBMC and exosome-derived Hotair is a critical regulator and potent marker for rheumatoid arthritis. Clin Exp Med. 2015;15:121–6.

    Article  CAS  PubMed  Google Scholar 

  13. Spurlock CF 3rd, Tossberg JT, Matlock BK, Olsen NJ, Aune TM. Methotrexate inhibits NF-kappaB activity via long intergenic (noncoding) RNA-p21 induction. Arthritis Rheumatol. 2014;66:2947–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.

    Article  CAS  PubMed  Google Scholar 

  15. Jordan ET, Collins M, Terefe J, Ugozzoli L, Rubio T. Optimizing electroporation conditions in primary and other difficult-to-transfect cells. J Biomol Tech. 2008;19:328–34.

    PubMed  PubMed Central  Google Scholar 

  16. Lu MC, Yu CL, Chen HC, Yu HC, Huang HB, Lai NS. Aberrant T cell expression of Ca2+ influx-regulated miRNAs in patients with systemic lupus erythematosus promotes lupus pathogenesis. Rheumatology. 2015;54:343–8.

    Article  PubMed  Google Scholar 

  17. Lu MC, Yu CL, Chen HC, Yu HC, Huang HB, Lai NS. Increased miR-223 expression in T cells from patients with rheumatoid arthritis leads to decreased insulin-like growth factor-1-mediated interleukin-10 production. Clin Exp Immunol. 2014;177:641–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625–39.

    Article  CAS  Google Scholar 

  19. Krishnan J, Mishra RK. Emerging trends of long non-coding RNAs in gene activation. FEBS J. 2014;281:34–45.

    Article  CAS  PubMed  Google Scholar 

  20. Church LD, Hessler G, Goodall JE, Rider DA, Workman CJ, Vignali DA, et al. TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-operated Ca2+ influx. J Leukoc Biol. 2005;78:266–78.

    Article  CAS  PubMed  Google Scholar 

  21. Stoffel B, Bauer P, Nix M, Deres K, Stoffel W. Ceramide-independent CD28 and TCR signaling but reduced IL-2 secretion in T cells of acid sphingomyelinase-deficient mice. Eur J Immunol. 1998;28:874–80.

    Article  CAS  PubMed  Google Scholar 

  22. Herz J, Pardo J, Kashkar H, Schramm M, Kuzmenkina E, Bos E, et al. Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat Immunol. 2009;10:761–8.

    Article  CAS  PubMed  Google Scholar 

  23. Brenner B, Ferlinz K, Grassmé H, Weller M, Koppenhoefer U, Dichgans J, et al. Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases. Cell Death Differ. 1998;5:29–37.

    Article  CAS  PubMed  Google Scholar 

  24. Bai A, Moss A, Kokkotou E, Usheva A, Sun X, Cheifetz A, et al. CD39 and CD161 modulate Th17 responses in Crohn’s disease. J Immunol. 2014;193:3366–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Ministry of Science and Technology (MOST 104-2314-B-303-008-MY2), Taiwan.

Authors’ contribution

MCL, CLY, and NSL contributed to the concept and design of the study. HCY and HBH performed the experiments. MCL, CHT, MK, and NSL analyzed the data. MCL drafted the manuscript. MK and NSL critically revised the manuscript. All authors read and approved the manuscript.

Author information

Authors and Affiliations

  1. Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Minsheng Road, Dalin, Chiayi, 62247, Taiwan

    Ming-Chi Lu, Hui-Chun Yu, Chien-Hsueh Tung & Ning-Sheng Lai

  2. School of Medicine, Tzu Chi University, Hualien, Taiwan

    Ming-Chi Lu, Chien-Hsueh Tung & Ning-Sheng Lai

  3. Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chiayi, Taiwan

    Hui-Chun Yu & Malcolm Koo

  4. Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

    Chia-Li Yu

  5. Department of Life Science, Institute of Molecular Biology, National Chung Cheng University, Minhsiung, Chiayi, Taiwan

    Hsien-Bin Huang

  6. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    Malcolm Koo

Authors
  1. Ming-Chi Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui-Chun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chia-Li Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hsien-Bin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Malcolm Koo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chien-Hsueh Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ning-Sheng Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ning-Sheng Lai.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, MC., Yu, HC., Yu, CL. et al. Increased expression of long noncoding RNAs LOC100652951 and LOC100506036 in T cells from patients with rheumatoid arthritis facilitates the inflammatory responses. Immunol Res 64, 576–583 (2016). https://doi.org/10.1007/s12026-015-8756-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-015-8756-8

Keywords

Search

Navigation