Original Article
 

Interleukin-21 Is Associated with the Pathogenesis of Lumbar Disc Herniation

Abstract

Inflammation is an important reaction underlying lumbar disc herniation (LDH). Th17 cells play a critical role in immune activation. Interleukin (IL)-21 controls the functional activity of effector T-helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. It plays important roles in chronic inflammation and autoimmune diseases. However, little is known about relationship between IL-21 and LDH. This study was aimed to  determine  the  association  between  IL-21  levels  and  pain  scores  in  LDH  patients compared to healthy controls.We enrolled 34 LDH patients and 20 healthy controls in this study. The LDH patients underwent surgery. Pain intensity was recorded using visual analogue scale (VAS) scores preoperatively. Serum IL-21 and IL-17 levels in the peripheral blood were determined using enzyme-linked immunosorbent assay. Disc tissue was examined using western blot and quantitative reverse-transcription polymerase chain reaction to determine IL-21, IL-17, and cyclooxygenase (COX)-2 expression, and using immunohistochemistry to assess IL-21 expression.LDH patients exhibited significantly higher levels of serum IL-21 and IL-17 than healthy controls. Moreover, higher expression of IL-21, IL-17, and COX-2 was found in the protein and mRNA levels in disc tissues from LDH patients than in normal disc tissues. Different parameters like VAS pain scores, IL-17, and COX-2 were positively correlated with the IL-21 levels. Enhanced production of IL-21 in disc tissues of LDH patients was also confirmed using immunohistochemical analyses.We concluded that inflammation was responsible for the pain associated with LDH, and that increased IL-21 expression may be associated with the pathogenesis of LDH.

1. Gilbertson L, Ahn SH, Teng PN, Studer RK, Niyibizi C, Kang JD. The effects of recombinant human bone morphogenetic protein-2, recombinant human bone morphogenetic protein-12, and adenoviral bone morphogenetic protein-12 on matrix synthesis in human annulus fibrosis and nucleus pulposus cells. Spine J 2008;8(3):449-56.

2. Schwarzer AC, Aprill CN, Derby R, Fortin J, Kine G, Bogduk N. The prevalence and clinical features of internal disc disruption in patients with chronic low back pain. Spine (Phila Pa 1976; 20(17):1878-83.

3. de Souza Grava AL, Ferrari LF, Defino HL. Cytokine inhibition and time-related influence of inflammatory stimuli on the hyperalgesia induced by the nucleus pulposus. Eur Spine J 2012; 21(3):537-45.

4. Kim HJ, Yeom JS, Koh YG, Yeo JE, Kang KT, Kang YM, Chang BS, Lee CK. Anti-inflammatory effect of platelet- rich plasma on nucleus pulposus cells with response of TNF-α and IL-1. J Orthop Res 2014; 32(4):551-6.

5. Weiler C, Nerlich AG, Bachmeier BE, Boos N. Expression and distribution of tumor necrosis factor alpha in human lumbar intervertebral discs: a study in surgical specimen and autopsy controls. Spine (Phila Pa 1976) 2005;30(1):44-53.

6. Kepler CK, Markova DZ, Dibra F, Yadla S, Vaccaro AR, Risbud MV, et al. Expression and relationship of proinflammatory chemokine RANTES/CCL5 and cytokine IL-1β in painful human intervertebral discs. Spine (Phila Pa 1976) 2013; 38(11):873-80.

7. Kraychete DC, Sakata RK, Issy AM, Bacellar O, Santos- Jesus R, Carvalho EM. Serum cytokine levels in patients with chronic low back pain due to herniated disc: analytical cross-sectional study. Sao Paulo Med J 2010;128(5):259-62.

8. Saal JS, Franson RC, Dobrow R, Saal JA, White AH, Goldthwaite N. High levels of inflammatory phospholipase A2 activity in lumbar disc herniations. Spine (Phila Pa 1976) 1990; 15(7):674-8.

9. O'Donnell JL, O'Donnell AL. Prostaglandin E2 content in herniated lumbar disc disease. Spine (Phila Pa 1976)1996; 21(14):1653-5.

10. Miyamoto H, Saura R, Harada T, Doita M, Mizuno K.The role of cyclooxygenase-2 and inflammatory cytokines in pain induction of herniated lumbar intervertebral disc. Kobe J Med Sci 2000; 46(1-2):13-28.

11. Kawakami M, Tamaki T, Hayashi N, Hashizume H, Nishi H. Possible mechanism of painful radiculopathy in lumbar disc herniation. Clin Orthop Relat Res 1998; (351):241-51.

12. Karppinen J, Daavittila I, Noponen N, Haapea M, Taimela S, Vanharanta H, et al. Is the interleukin-6 haplotype a prognostic factor for sciatica? Eur J Pain 2008; 12(8):1018-25.

13. Gabr MA, Jing L, Helbling AR, Sinclair SM, Allen KD, Shamji MF, et al. Interleukin-17 synergizes with IFNγ or TNFα to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells. J Orthop Res 2011;29(1):1-7.

14. Cheng L, Fan W, Liu B, Wang X, Nie L. Th17 lymphocyte levels are higher in patients with ruptured than non-ruptured lumbar discs, and are correlated with pain intensity. Injury 2013; 44(12):1805-10.

15.Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000; 408(6808):57-63.

16. Doganci A, Birkholz J, Gehring S, Puhl AG, Zepp F, Meyer CU. In the presence of IL-21 human cord blood T cells differentiate to IL-10-producing Th1 but not Th17 or Th2 cells. Int Immunol 2013; 25(3):157-69.

17. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol 2008; 26:57-79.

18. Nguyen V, Luzina I, Rus H, Tegla C, Chen C, Rus V. IL-21 promotes lupus-like disease in chronic graft-versus-host disease through both CD4 T cell- and B cell-intrinsic mechanisms. J Immunol 2012; 189(2):1081-93.

19. Ettinger R, Sims GP, Robbins R, Withers D, Fischer RT, Grammer AC, et al. IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells. J Immunol 2007; 178(5):2872-82.

20. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 2004; 173(9):5361-71.

21. Dolff S, Abdulahad WH, Westra J, Doornbos-van der Meer B, Limburg PC, Kallenberg CG, et al. Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus. Arthritis Res Ther 2011; 13(5):R157.

22. Gottenberg JE, Dayer JM, Lukas C, Ducot B, Chiocchia G, Cantagrel A, et al. Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis: results from the ESPOIR cohort. Ann Rheum Dis 2012; 71(7):1243-8.

23. Scofield RH. IL-21 and Sjögren's syndrome. Arthritis Res Ther 2011; 13(6):137.

24. Tzartos JS, Craner MJ, Friese MA, Jakobsen KB, Newcombe J, Esiri MM, et al. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol 2011; 178(2):794-802.

25.Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ.IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proc Natl Acad Sci U S A 2008; 105(37):14028-33.

26. Macnab I. Cervical spondylosis. Clin Orthop Relat Res 1975; (109):69-77.

27. Di Martino A, Merlini L, Faldini C. Autoimmunity in intervertebral disc herniation: from bench to bedside. Expert Opin Ther Targets 2013; 17(12):1461-70.

28. atoh K, Konno S, Nishiyama K, Olmarker K, Kikuchi S.Presence and distribution of antigen-antibody complexes in the herniated nucleus pulposus. Spine (Phila Pa 1976)1999; 24(19):1980-4.

29. Arai Y, Yasuma T, Shitoto K, Yamauchi Y, Suzuki F.Immunohistological study of intervertebral disc herniation of lumbar spine. J Orthop Sci 2000; 5(3):229-31.

30. Geiss A, Larsson K, Rydevik B, Takahashi I, Olmarker K. Autoimmune properties of nucleus pulposus: an experimental study in pigs. Spine (Phila Pa 1976) 2007;32(2):168-73.

31. Murai K, Sakai D, Nakamura Y, Nakai T, Igarashi T, Seo N, et al. Primary immune system responders to nucleus pulposus cells: evidence for immune response in disc herniation. Eur Cell Mater 2010; 19:13-21.

32. Naylor A, Happey F, Turner RL, Shentall RD, West DC, Richardson C. Enzymic and immunological activity in the intervertebral disk. Orthop Clin North Am 1975; 6(1):51-8.

33. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci U S A 2000; 97(21):11439-44.

34. Caruso R, Botti E, Sarra M, Esposito M, Stolfi C, Diluvio L, et al. Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat Med 2009; 15(9):1013-5.

35. Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007;448(7152):484-7.

36. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007;448(7152):480-3.

37. Korn T, Oukka M, Kuchroo V, Bettelli E. Th17 cells: effector T cells with inflammatory properties. Semin Immunol 2007; 19(6):362-71.

38. Wei L, Laurence A, Elias KM, O'Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 2007;282(48):34605 -10.

39. Geri G, Terrier B, Rosenzwajg M, Wechsler B, Touzot M, Seilhean D, et al. Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease. J Allergy Clin Immunol 2011; 128(3):655-64.

40. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007;8(9):967-74.

41. Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 2005; 201(1):139-48.

42. Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J Immunol 2007;178(6):3822-30.

43. Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 2007;56(4):1152-63.

44. Sutherland AP, Van Belle T, Wurster AL, Suto A, Michaud M, Zhang D, et al. Interleukin-21 is required for the development of type 1 diabetes in NOD mice. Diabetes 2009; 58(5):1144-55.

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IssueVol 14, No 5 (2015) QRcode
SectionOriginal Article(s)
Keywords
COX-2 IL-17 IL-21 Intervertebral disc Lumbar disc herniation

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How to Cite
1.
Xue H, Yao Y, Wang X, Zhang F, Jiang X, Liu J, Wang H, Li Y, Wang X, Li H, Zhang J. Interleukin-21 Is Associated with the Pathogenesis of Lumbar Disc Herniation. Iran J Allergy Asthma Immunol. 2015;14(5):509-518.