Top

Published in:

Open Access 01-10-2010 | Research article

Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression

Authors: Leigh D Church, Andrew D Filer, Esther Hidalgo, Katherine A Howlett, Andrew MC Thomas, Stephen Rapecki, Dagmar Scheel-Toellner, Christopher D Buckley, Karim Raza

Published in: Arthritis Research & Therapy | Issue 5/2010

Abstract

Introduction

Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to systematically analyse the phenotype, cytokine profile and frequency of interleukin-17 (IL-17) producing CD4-positive T cells in mononuclear cells isolated from peripheral blood, synovial fluid and synovial tissue of RA patients with established disease, and to correlate cell frequencies with disease activity.

Methods

Flow cytometry was used to analyse the phenotype and cytokine production of mononuclear cells isolated from peripheral blood (PBMC) (n = 44), synovial fluid (SFMC) (n = 14) and synovium (SVMC) (n = 10) of RA patients and PBMC of healthy controls (n = 13).

Results

The frequency of IL-17-producing CD4 T cells was elevated in RA SFMC compared with RA PBMC (P = 0.04). However, the frequency of this population in RA SVMC was comparable to that in paired RA PBMC. The percentage of IL-17-producing CD4 T cells coexpressing tumor necrosis factor alpha (TNFα) was significantly increased in SFMC (P = 0.0068). The frequency of IFNγ-producing CD4 T cells was also significantly higher in SFMC than paired PBMC (P = 0.042). The majority of IL-17-producing CD4 T cells coexpressed IFNγ. IL-17-producing CD4 T cells in RA PBMC and SFMC exhibited very little IL-22 or IL-23R coexpression.

Conclusions

These findings demonstrate a modest enrichment of IL-17-producing CD4 T cells in RA SFMC compared to PBMC. Th17 cells in SFMC produce more TNFα than their PBMC counterparts, but are not a significant source of IL-22 and do not express IL-23R. However, the percentage of CD4 T cells which produce IL-17 in the rheumatoid joint is low, suggesting that other cells may be alternative sources of IL-17 within the joints of RA patients.

Available only for authorised users

Firestein GS: Evolving concepts of rheumatoid arthritis. Nature. 2003, 423: 356-361. 10.1038/nature01661.PubMed

Morita Y, Yamamura M, Kawashima M, Harada S, Tsuji K, Shibuya K, Maruyama K, Makino H: Flow cytometric single-cell analysis of cytokine production by CD4+ T cells in synovial tissue and peripheral blood from patients with rheumatoid arthritis. Arthritis Rheum. 1998, 41: 1669-1676. 10.1002/1529-0131(199809)41:9<1669::AID-ART19>3.0.CO;2-G.PubMed

Simon AK, Seipelt E, Sieper J: Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA. 1994, 91: 8562-8566. 10.1073/pnas.91.18.8562.PubMedPubMedCentral

Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT: Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005, 6: 1123-1132. 10.1038/ni1254.PubMed

Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C: A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005, 6: 1133-1141. 10.1038/ni1261.PubMedPubMedCentral

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL: Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986, 136: 2348-2357.PubMed

Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ: Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003, 198: 1951-1957. 10.1084/jem.20030896.PubMedPubMedCentral

Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D: IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006, 116: 1310-1316. 10.1172/JCI21404.PubMedPubMedCentral

Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W: Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007, 445: 648-651. 10.1038/nature05505.PubMed

10.

Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006, 441: 235-238. 10.1038/nature04753.PubMed

11.

Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR: The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006, 126: 1121-1133. 10.1016/j.cell.2006.07.035.PubMed

12.

Veldhoen M, Hirota K, Christensen J, O'Garra A, Stockinger B: Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med. 2009, 206: 43-49. 10.1084/jem.20081438.PubMedPubMedCentral

13.

Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B: The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008, 453: 106-109. 10.1038/nature06881.PubMed

14.

Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM: 1,25-Dihydroxyvitamin D(3) and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 2009, 183: 5458-5467. 10.4049/jimmunol.0803217.PubMed

15.

Colin EM, Asmawidjaja PS, van Hamburg JP, Mus AM, van Driel M, Hazes JM, van Leeuwen JP, Lubberts E: 1,25-dihydroxyvitamin D(3) modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum. 2010, 62: 132-142. 10.1002/art.25043.PubMed

16.

Iwakura Y, Nakae S, Saijo S, Ishigame H: The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev. 2008, 226: 57-79. 10.1111/j.1600-065X.2008.00699.x.PubMed

17.

Aarvak T, Chabaud M, Miossec P, Natvig JB: IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol. 1999, 162: 1246-1251.PubMed

18.

Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P: Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999, 42: 963-970. 10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E.PubMed

19.

Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999, 103: 1345-1352. 10.1172/JCI5703.PubMedPubMedCentral

20.

Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN, Lord JM, Gordon C, Buckley CD, Salmon M: Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005, 7: R784-R795. 10.1186/ar1733.PubMedPubMedCentral

21.

Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, Maslinski W: High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol. 2000, 164: 2832-2838.PubMed

22.

Fossiez F, Djossou O, Chomarat P, Flores-Romo L, Ait-Yahia S, Maat C, Pin JJ, Garrone P, Garcia E, Saeland S, Blanchard D, Gaillard C, Das MB, Rouvier E, Golstein P, Banchereau J, Lebecque S: T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med. 1996, 183: 2593-2603. 10.1084/jem.183.6.2593.PubMed

23.

Parsonage G, Filer A, Bik M, Hardie D, Lax S, Howlett K, Church LD, Raza K, Wong SH, Trebilcock E, Scheel-Toellner D, Salmon M, Lord JM, Buckley CD: Prolonged, granulocyte-macrophage colony-stimulating factor-dependent, neutrophil survival following rheumatoid synovial fibroblast activation by IL-17 and TNFalpha. Arthritis Res Ther. 2008, 10: R47-10.1186/ar2406.PubMedPubMedCentral

24.

van den Berg WB, Miossec P: IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol. 2009, 5: 549-553. 10.1038/nrrheum.2009.179.PubMed

25.

Shen H, Goodall JC, Hill Gaston JS: Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 2009, 60: 1647-1656. 10.1002/art.24568.PubMed

26.

Shahrara S, Huang Q, Mandelin AM, Pope RM: TH-17 cells in rheumatoid arthritis. Arthritis Res Ther. 2008, 10: R93-10.1186/ar2477.PubMedPubMedCentral

27.

Nistala K, Moncrieffe H, Newton KR, Varsani H, Hunter P, Wedderburn LR: Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum. 2008, 58: 875-887. 10.1002/art.23291.PubMedPubMedCentral

28.

Yamada H, Nakashima Y, Okazaki K, Mawatari T, Fukushi JI, Kaibara N, Hori A, Iwamoto Y, Yoshikai Y: Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Ann Rheum Dis. 2008, 67: 1299-1304. 10.1136/ard.2007.080341.PubMed

29.

Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988, 31: 315-324. 10.1002/art.1780310302.PubMed

30.

Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA: Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006, 203: 2271-2279. 10.1084/jem.20061308.PubMedPubMedCentral

31.

Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal MR: Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007, 8: 950-957. 10.1038/ni1497.PubMed

32.

Geboes L, Dumoutier L, Kelchtermans H, Schurgers E, Mitera T, Renauld JC, Matthys P: Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum. 2009, 60: 390-395. 10.1002/art.24220.PubMed

33.

Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, Ueki K, Nojima Y: Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 2005, 52: 1037-1046. 10.1002/art.20965.PubMed

34.

Kirkham BW, Lassere MN, Edmonds JP, Juhasz KM, Bird PA, Lee CS, Shnier R, Portek IJ: Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum. 2006, 54: 1122-1131. 10.1002/art.21749.PubMed

35.

Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H: Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006, 203: 2673-2682. 10.1084/jem.20061775.PubMedPubMedCentral

36.

Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S: Phenotypic and functional features of human Th17 cells. J Exp Med. 2007, 204: 1849-1861. 10.1084/jem.20070663.PubMedPubMedCentral

37.

Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, Melendez AJ, McInnes IB: Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol. 2010, 184: 3336-3340. 10.4049/jimmunol.0903566.PubMed

38.

Volpe E, Touzot M, Servant N, Marloie-Provost MA, Hupe P, Barillot E, Soumelis V: Multiparametric analysis of cytokine-driven human Th17 differentiation reveals a differential regulation of IL-17 and IL-22 production. Blood. 2009, 114: 3610-3614. 10.1182/blood-2009-05-223768.PubMed

39.

Lecart S, Morel F, Noraz N, Pene J, Garcia M, Boniface K, Lecron JC, Yssel H: IL-22, in contrast to IL-10, does not induce Ig production, due to absence of a functional IL-22 receptor on activated human B cells. Int Immunol. 2002, 14: 1351-1356. 10.1093/intimm/dxf096.PubMed

40.

Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K, Volk HD, Sterry W, Sabat R: IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol. 2006, 36: 1309-1323. 10.1002/eji.200535503.PubMed

41.

Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, Tsujikawa T, Kitoh K, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y: Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005, 129: 969-984. 10.1053/j.gastro.2005.06.071.PubMed

42.

Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, Diepolder H, Marquardt A, Jagla W, Popp A, Leclair S, Herrmann K, Seiderer J, Ochsenkuhn T, Goke B, Auernhammer CJ, Dambacher J: IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006, 290: G827-G838. 10.1152/ajpgi.00513.2005.PubMed

43.

Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F: Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009, 10: 857-863. 10.1038/ni.1767.PubMed

44.

Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H: Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009, 10: 864-871. 10.1038/ni.1770.PubMed

45.

Mus AM, Cornelissen F, Asmawidjaja PS, van Hamburg JP, Boon L, Hendriks RW, Lubberts E: Interleukin-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of interleukin-22, but not interleukin-21, in autoimmune experimental arthritis. Arthritis Rheum. 2010, 62: 1043-1050. 10.1002/art.27336.PubMed

46.

Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V: A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008, 9: 650-657. 10.1038/ni.1613.PubMed

47.

Brentano F, Ospelt C, Stanczyk J, Gay RE, Gay S, Kyburz D: Abundant expression of the interleukin (IL)23 subunit p19, but low levels of bioactive IL23 in the rheumatoid synovium: differential expression and Toll-like receptor-(TLR) dependent regulation of the IL23 subunits, p19 and p40, in rheumatoid arthritis. Ann Rheum Dis. 2009, 68: 143-150. 10.1136/ard.2007.082081.PubMed

48.

Mitoma H, Horiuchi T, Tsukamoto H, Tamimoto Y, Kimoto Y, Uchino A, To K, Harashima S, Hatta N, Harada M: Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum. 2008, 58: 1248-1257. 10.1002/art.23447.PubMed

49.

Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y, Otsuka J, Okamura S, Fujita S, Harada M: Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology. 2005, 128: 376-392. 10.1053/j.gastro.2004.11.060.PubMed

50.

Shen C, Maerten P, Geboes K, Van Assche G, Rutgeerts P, Ceuppens JL: Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model. Clin Immunol. 2005, 115: 250-259. 10.1016/j.clim.2005.01.007.PubMed

51.

Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y: IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006, 177: 566-573.PubMed

52.

Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L: Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008, 172: 146-155. 10.2353/ajpath.2008.070690.PubMedPubMedCentral

Title: Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression
Authors: Leigh D Church
Andrew D Filer
Esther Hidalgo
Katherine A Howlett
Andrew MC Thomas
Stephen Rapecki
Dagmar Scheel-Toellner
Christopher D Buckley
Karim Raza
Publication date: 01-10-2010
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 5/2010
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/ar3152

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression

Abstract

Introduction

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2010

Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy

Bone and cartilage in osteoarthritis: is what's best for one good or bad for the other?

Influence of comorbidity with depression on interdisciplinary therapy: outcomes in patients with chronic low back pain

Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study

Autoantibodies to BRAF, a new family of autoantibodies associated with rheumatoid arthritis

Interleukin-6: a local pain trigger?

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page