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Erschienen in: Clinical Rheumatology 11/2019

25.07.2019 | Original Article

The expression of GAS5, THRIL, and RMRP lncRNAs is increased in T cells of patients with rheumatoid arthritis

verfasst von: Mozhgan Moharamoghli, Vahideh Hassan-Zadeh, Elahe Dolatshahi, Zahra Alizadeh, Ali Farazmand

Erschienen in: Clinical Rheumatology | Ausgabe 11/2019

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Abstract

Objective

Long non-coding RNAs (lncRNAs) comprise a large and diverse group of non-coding RNAs (ncRNAs) with important regulatory roles in various biological processes, including the immune system regulation. Rheumatoid arthritis (RA) as an autoimmune disease initiates inflammation in the synovial joints. T cells infiltrating into the synovial membrane have an important role in the pathogenesis of RA. The aim of the current investigation was to analyze the expression of four lncRNAs in the T cells from RA patients and healthy controls.

Methods

In the current study, we investigated the expression of GAS5, RMRP, IFNϒ-AS1, and THRIL lncRNAs in circulating T cells from 20 patients with RA and 18 healthy matched controls by quantitative real-time PCR. T cell isolation was accomplished using the MAC method. We also analyzed the correlation between lncRNA expression and clinical parameters. Also, the mRNA expression levels of IL-17 and TNF-α and the association between lncRNAs and these cytokines were examined.

Results

The results indicate that T cells of RA patients display increased levels of GAS5 (3.31-fold, p = 0.007), RMRP (2.43-fold, p = 0.02), and THRIL (2.14-fold, p = 0.03) lncRNAs compared with those of controls. Furthermore, a positive correlation was found between RMRP expression and disease duration in RA. Receiver operating characteristic (ROC) curve of GAS5, RMRP, and THRIL has a discriminative value in comparing RA patients and controls.

Conclusion

The results suggest lncRNAs may be involved in T cell dysfunction in RA. Further studies are required to see whether these lncRNAs have an effect on dysregulation of immune responses in RA disease.
Key Points
70% of non-coding sequences in the human genome are transcribed to RNA.
A growing body of evidence shows the importance of lncRNAs in innate and adaptive immune cell differentiation and functions.
Important recent works suggest a key role of immune cell lncRNAs in autoimmune processes and diseases including RA.
Literatur
2.
Zurück zum Zitat Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E (2014) Diagnosis and classification of rheumatoid arthritis. J Autoimmun 49:26–30CrossRef Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E (2014) Diagnosis and classification of rheumatoid arthritis. J Autoimmun 49:26–30CrossRef
4.
Zurück zum Zitat Croia C, Bursi R, Sutera D, Petrelli F, Alunno A, Puxeddu I (2019) One year in review 2019: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 37(3):347–357PubMed Croia C, Bursi R, Sutera D, Petrelli F, Alunno A, Puxeddu I (2019) One year in review 2019: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 37(3):347–357PubMed
5.
Zurück zum Zitat MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, Silman AJ (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43(1):30–37 MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, Silman AJ (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43(1):30–37
8.
Zurück zum Zitat Cope AP, Schulze-Koops H, Aringer M (2007) The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol 25(5 Suppl 46):S4–S11 Cope AP, Schulze-Koops H, Aringer M (2007) The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol 25(5 Suppl 46):S4–S11
9.
Zurück zum Zitat Lubberts E (2015) Role of T lymphocytes in the development of rheumatoid arthritis. Implications for treatment. Curr Pharm Des 21(2):142–146CrossRef Lubberts E (2015) Role of T lymphocytes in the development of rheumatoid arthritis. Implications for treatment. Curr Pharm Des 21(2):142–146CrossRef
10.
Zurück zum Zitat Gaffen SL (2009) The role of interleukin-17 in the pathogenesis of rheumatoid arthritis. Curr Rheumatol Rep 11(5):365–370CrossRef Gaffen SL (2009) The role of interleukin-17 in the pathogenesis of rheumatoid arthritis. Curr Rheumatol Rep 11(5):365–370CrossRef
11.
Zurück zum Zitat Boissier MC, Assier E, Biton J, Denys A, Falgarone G, Bessis N (2009) Regulatory T cells (Treg) in rheumatoid arthritis. Joint Bone Spine 76(1):10–14CrossRef Boissier MC, Assier E, Biton J, Denys A, Falgarone G, Bessis N (2009) Regulatory T cells (Treg) in rheumatoid arthritis. Joint Bone Spine 76(1):10–14CrossRef
14.
Zurück zum Zitat Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10(3):155–159CrossRef Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10(3):155–159CrossRef
15.
Zurück zum Zitat Mowel WK, Kotzin JJ, McCright SJ, Neal VD, Henao-Mejia J (2018) Control of immune cell homeostasis and function by lncRNAs. Trends Immunol 39(1):55–69CrossRef Mowel WK, Kotzin JJ, McCright SJ, Neal VD, Henao-Mejia J (2018) Control of immune cell homeostasis and function by lncRNAs. Trends Immunol 39(1):55–69CrossRef
16.
Zurück zum Zitat Chen YG, Satpathy AT, Chang HY (2017) Gene regulation in the immune system by long noncoding RNAs. Nat Immunol 18(9):962–972CrossRef Chen YG, Satpathy AT, Chang HY (2017) Gene regulation in the immune system by long noncoding RNAs. Nat Immunol 18(9):962–972CrossRef
17.
Zurück zum Zitat Heward JA, Lindsay MA (2014) Long non-coding RNAs in the regulation of the immune response. Trends Immunol 35(9):408–419CrossRef Heward JA, Lindsay MA (2014) Long non-coding RNAs in the regulation of the immune response. Trends Immunol 35(9):408–419CrossRef
18.
Zurück zum Zitat Aune TM, Crooke PS 3rd, Spurlock CF 3rd (2016) Long noncoding RNAs in T lymphocytes. J Leukoc Biol 99(1):31–44CrossRef Aune TM, Crooke PS 3rd, Spurlock CF 3rd (2016) Long noncoding RNAs in T lymphocytes. J Leukoc Biol 99(1):31–44CrossRef
20.
Zurück zum Zitat Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TWJ, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581. https://doi.org/10.1002/art.27584 CrossRef Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TWJ, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581. https://​doi.​org/​10.​1002/​art.​27584 CrossRef
24.
Zurück zum Zitat Wu GC, Pan HF, Leng RX, Wang DG, Li XP, Li XM, Ye DQ (2015) Emerging role of long noncoding RNAs in autoimmune diseases. Autoimmun Rev 14(9):798–805CrossRef Wu GC, Pan HF, Leng RX, Wang DG, Li XP, Li XM, Ye DQ (2015) Emerging role of long noncoding RNAs in autoimmune diseases. Autoimmun Rev 14(9):798–805CrossRef
25.
Zurück zum Zitat Zhang HJ, Wei QF, Wang SJ, Zhang XY, Geng Q, Cui YH, Wang XH (2017) LncRNA HOTAIR alleviates rheumatoid arthritis by targeting miR-138 and inactivating NF-kappaB pathway. Int Immunopharmacol 50:283–290CrossRef Zhang HJ, Wei QF, Wang SJ, Zhang XY, Geng Q, Cui YH, Wang XH (2017) LncRNA HOTAIR alleviates rheumatoid arthritis by targeting miR-138 and inactivating NF-kappaB pathway. Int Immunopharmacol 50:283–290CrossRef
27.
Zurück zum Zitat Stuhlmuller B, Kunisch E, Franz J, Martinez-Gamboa L, Hernandez MM, Pruss A, Ulbrich N, Erdmann VA, Burmester GR, Kinne RW (2003) Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue. Am J Pathol 163(3):901–911CrossRef Stuhlmuller B, Kunisch E, Franz J, Martinez-Gamboa L, Hernandez MM, Pruss A, Ulbrich N, Erdmann VA, Burmester GR, Kinne RW (2003) Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue. Am J Pathol 163(3):901–911CrossRef
28.
Zurück zum Zitat Pickard MR, Williams GT (2015) Molecular and cellular mechanisms of action of tumour suppressor GAS5 LncRNA. Genes 6(3):484–499CrossRef Pickard MR, Williams GT (2015) Molecular and cellular mechanisms of action of tumour suppressor GAS5 LncRNA. Genes 6(3):484–499CrossRef
29.
Zurück zum Zitat Gutschner T, Diederichs S (2012) The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol 9(6):703–719CrossRef Gutschner T, Diederichs S (2012) The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol 9(6):703–719CrossRef
30.
Zurück zum Zitat Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP (2010) Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 3(107):2000568 Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP (2010) Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 3(107):2000568
31.
Zurück zum Zitat Lucafo M, Bravin V, Tommasini A, Martelossi S, Rabach I, Ventura A, Decorti G, De Iudicibus S (2016) Differential expression of GAS5 in rapamycin-induced reversion of glucocorticoid resistance. Clin Exp Pharmacol Physiol 43(6):602–605CrossRef Lucafo M, Bravin V, Tommasini A, Martelossi S, Rabach I, Ventura A, Decorti G, De Iudicibus S (2016) Differential expression of GAS5 in rapamycin-induced reversion of glucocorticoid resistance. Clin Exp Pharmacol Physiol 43(6):602–605CrossRef
32.
Zurück zum Zitat Chang DD, Clayton DA (1987) A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication. EMBO J 6(2):409–417CrossRef Chang DD, Clayton DA (1987) A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication. EMBO J 6(2):409–417CrossRef
33.
Zurück zum Zitat Meng Q, Ren M, Li Y, Song X (2016) LncRNA-RMRP acts as an oncogene in lung cancer. PLoS One 11(12):e0164845CrossRef Meng Q, Ren M, Li Y, Song X (2016) LncRNA-RMRP acts as an oncogene in lung cancer. PLoS One 11(12):e0164845CrossRef
34.
Zurück zum Zitat Shao Y, Ye M, Li Q, Sun W, Ye G, Zhang X, Yang Y, Xiao B, Guo J (2016) LncRNA-RMRP promotes carcinogenesis by acting as a miR-206 sponge and is used as a novel biomarker for gastric cancer. Oncotarget 7(25):37812–37824CrossRef Shao Y, Ye M, Li Q, Sun W, Ye G, Zhang X, Yang Y, Xiao B, Guo J (2016) LncRNA-RMRP promotes carcinogenesis by acting as a miR-206 sponge and is used as a novel biomarker for gastric cancer. Oncotarget 7(25):37812–37824CrossRef
35.
Zurück zum Zitat Huang W, Thomas B, Flynn RA, Gavzy SJ, Wu L, Kim SV, Hall JA, Miraldi ER, Ng CP, Rigo F, Meadows S, Montoya NR, Herrera NG, Domingos AI, Rastinejad F, Myers RM, Fuller-Pace FV, Bonneau R, Chang HY, Acuto O, Littman DR (2015) DDX5 and its associated lncRNA Rmrp modulate Th17 cell effector functions. Nature 528(7583):517–522. https://doi.org/10.1038/nature16193 CrossRefPubMedPubMedCentral Huang W, Thomas B, Flynn RA, Gavzy SJ, Wu L, Kim SV, Hall JA, Miraldi ER, Ng CP, Rigo F, Meadows S, Montoya NR, Herrera NG, Domingos AI, Rastinejad F, Myers RM, Fuller-Pace FV, Bonneau R, Chang HY, Acuto O, Littman DR (2015) DDX5 and its associated lncRNA Rmrp modulate Th17 cell effector functions. Nature 528(7583):517–522. https://​doi.​org/​10.​1038/​nature16193 CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, Skapenko A (2010) Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 62(10):2876–2885CrossRef Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, Skapenko A (2010) Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 62(10):2876–2885CrossRef
37.
Zurück zum Zitat Gomez JA, Wapinski OL, Yang YW, Bureau JF, Gopinath S, Monack DM, Chang HY, Brahic M, Kirkegaard K (2013) The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell 152(4):743–754CrossRef Gomez JA, Wapinski OL, Yang YW, Bureau JF, Gopinath S, Monack DM, Chang HY, Brahic M, Kirkegaard K (2013) The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell 152(4):743–754CrossRef
40.
Zurück zum Zitat Lee SH, Kwon JY, Kim SY, Jung K, Cho ML (2017) Interferon-gamma regulates inflammatory cell death by targeting necroptosis in experimental autoimmune arthritis. Sci Rep 7(1):017–09767CrossRef Lee SH, Kwon JY, Kim SY, Jung K, Cho ML (2017) Interferon-gamma regulates inflammatory cell death by targeting necroptosis in experimental autoimmune arthritis. Sci Rep 7(1):017–09767CrossRef
42.
Zurück zum Zitat Li Z, Chao TC, Chang KY, Lin N, Patil VS, Shimizu C, Head SR, Burns JC, Rana TM (2014) The long noncoding RNA THRIL regulates TNFalpha expression through its interaction with hnRNPL. Proc Natl Acad Sci U S A 111(3):1002–1007CrossRef Li Z, Chao TC, Chang KY, Lin N, Patil VS, Shimizu C, Head SR, Burns JC, Rana TM (2014) The long noncoding RNA THRIL regulates TNFalpha expression through its interaction with hnRNPL. Proc Natl Acad Sci U S A 111(3):1002–1007CrossRef
Metadaten
Titel
The expression of GAS5, THRIL, and RMRP lncRNAs is increased in T cells of patients with rheumatoid arthritis
verfasst von
Mozhgan Moharamoghli
Vahideh Hassan-Zadeh
Elahe Dolatshahi
Zahra Alizadeh
Ali Farazmand
Publikationsdatum
25.07.2019
Verlag
Springer London
Erschienen in
Clinical Rheumatology / Ausgabe 11/2019
Print ISSN: 0770-3198
Elektronische ISSN: 1434-9949
DOI
https://doi.org/10.1007/s10067-019-04694-z

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