臨床整形外科53巻11号

2018年11月発行

誌上シンポジウム 椎間板研究の最前線

椎間板変性と炎症

著者： 高田徹¹² 角谷賢一朗² 由留部崇² 張鍾穎³ 宮崎真吾² 黒田良祐² 西田康太郎³

所属機関： ¹医療法人社団健心会神戸ほくと病院脊椎センター ²神戸大学大学院整形外科 ³神戸大学大学院整形外科脊椎外科部門

ページ範囲：P.951 - P.957

　椎間板は無血管組織ゆえの物理的バリアーと免疫学的特権を有する組織である．椎間板変性の過程で宿主免疫に曝露され，炎症反応を生じる．宿主免疫の中でも，マクロファージと椎間板組織との相互作用は，TNFα依存性炎症(IL-6，PGE₂産生)とTNFα非依存性炎症(IL-8産生)を生じ，疼痛関連行動を惹起していた．椎間板変性と炎症をマクロファージと椎間板の相互作用とそれによって起きる炎症を中心に解説する．

参考文献

1) Cuéllar JM, Borges PM, Cuéllar VG, et al. Cytokine expression in the epidural space:a model of noncompressive disc herniation-induced inflammation. Spine (Phila Pa 1976) 2013;38:17-23.

2) van der Windt DA, Simons E, Riphagen II, et al. Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain. Cochrane Database Syst Rev 2010;(2):CD007431. doi:10.1002/14651858.CD007431.pub2.

3) 日本整形外科学会，日本脊椎脊髄病学会(監修)，日本整形外科学会診療ガイドライン委員会・他(編)．腰椎椎間板ヘルニア診療ガイドライン改定第2版．東京：南江堂；2011．

4) National Center for Biotechnology Information USNLoM. What is an inflammation? January 7, 2015 [2018/08/17].

5) Bobechko WP, Hirsch C. Auto-immune response to nucleus pulposus in the rabbit. J Bone Joint Surg Br 1965;47:574-80.

6) Gertzbein SD, Tait JH, Devlin SR. The stimulation of lymphocytes by nucleus pulposus in patients with degenerative disk disease of the lumbar spine. Clin Orthop Relat Res 1977;123:149-54.

7) Nishida K, Kang JD, Gilbertson LG, et al. Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy:an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene. Spine (Phila Pa 1976) 1999;24:2419-25.

8) Takada T, Nishida K, Doita M, et al. Fas ligand exists on intervertebral disc cells:a potential molecular mechanism for immune privilege of the disc. Spine (Phila Pa 1976) 2002;27:1526-30.

9) Survey of Medical Care Activities in Public Health Insurance 2017:Ministry of Health, Labour and Welfare. Accessed 10 Janualy 2018;[cited 2018]. Available from:https://www.e-stat.go.jp/stat-search/files?page=1＆layout=datalist＆toukei=00450048＆tstat=000001029602＆cycle=7＆year=20170＆month=0＆tclass1=000001116156＆tclass2=000001116157＆tclass3=000001116255 社会医療診療行為別統計．報告書1．診療行為・調剤行為の状況，2017(日本語).

10) Hoyland JA, Le Maitre C, Freemont AJ. Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc. Rheumatology (Oxford) 2008;47:809-14.

11) Yamamoto J, Maeno K, Takada T, et al. Fas ligand plays an important role for the production of pro-inflammatory cytokines in intervertebral disc nucleus pulposus cells. J Orthop Res 2013;31:608-15.

12) Shamji MF, Setton LA, Jarvis W, et al. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum 2010;62:1974-82.

13) Kanerva A, Kommonen B, Grönblad M, et al. Inflammatory cells in experimental intervertebral disc injury. Spine (Phila Pa 1976) 1997;22:2711-5.

14) Wiet MG, Piscioneri A, Khan SN, et al. Mast cell-intervertebral disc cell interactions regulate inflammation, catabolism and angiogenesis in discogenic back pain. Sci Rep 2017;7:12492. doi:10.1038/s41598-017-12666-z.

15) Grönblad M, Virri J, Seitsalo S, et al. Inflammatory cells, motor weakness, and straight leg raising in transligamentous disc herniations. Spine (Phila Pa 1976) 2000;25:2803-7.

16) Woertgen C, Rothoerl RD, Brawanski A. Influence of macrophage infiltration of herniated lumbar disc tissue on outcome after lumbar disc surgery. Spine 2000;25:871-5.

17) Doita M, Kanatani T, Harada T, et al. Immunohistologic study of the ruptured intervertebral disc of the lumbar spine. Spine (Phila Pa 1976) 1996;21:235-41.

18) Takada T, Nishida K, Doita M, et al. Interleukin-6 production is upregulated by interaction between disc tissue and macrophages. Spine (Phila Pa 1976) 2004;29:1089-92;discussion 1093.

19) Haro H, Crawford HC, Fingleton B, et al. Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption. J Clin Invest 2000;105:133-41.

20) Haro H, Crawford HC, Fingleton B, et al. Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption. J Clin Invest 2000;105:143-50.

21) Takada T, Nishida K, Maeno K, et al. Intervertebral disc and macrophage interaction induces mechanical hyperalgesia and cytokine production in a herniated disc model in rats. Arthritis Rheum 2012;64:2601-10.

22) Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008;8:958-69.

23) Rigamonti E, Zordan P, Sciorati C, et al. Macrophage plasticity in skeletal muscle repair. Biomed Res Int 2014;2014:560629. doi:10.1155/2014/560629

24) Lurier EB, Dalton D, Dampier W, et al. Transcriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing. Immunobiology 2017;222:847-56.

25) Nakazawa KR, Walter BA, Laudier DM, et al. Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration. Spine J 2018;18:343-56.

26) Ahn SH, Cho YW, Ahn MW, et al. mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Phila Pa 1976) 2002;27:911-7.

27) Le Maitre CL, Hoyland JA, Freemont AJ. Catabolic cytokine expression in degenerate and herniated human intervertebral discs:IL-1beta and TNFalpha expression profile. Arthritis Res Ther 2007;9:R77. doi:10.1186/ar2275.

28) Le Maitre CL, Freemont AJ, Hoyland JA. The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther 2005;7:R732-45. doi:10.1186/ar1732.

29) Burke JG, G Watson RW, Conhyea D, et al. Human nucleus pulposis can respond to a pro-inflammatory stimulus. Spine (Phila Pa 1976) 2003;28:2685-93.

30) Burke JG, Watson RW, McCormack D, et al. Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surg Br 2002;84:196-201.

31) Li H, Zou X, Baatrup A, et al. Cytokine profiles in conditioned media from cultured human intervertebral disc tissue. Implications of their effect on bone marrow stem cell metabolism. Acta Orthop 2005;76:115-21.

32) Burke JG, Watson RW, McCormack D, et al. Spontaneous production of monocyte chemoattractant protein-1 and interleukin-8 by the human lumbar intervertebral disc. Spine (Phila Pa 1976). 2002;27:1402-7.

33) Kang JD, Georgescu HI, McIntyre-Larkin L, et al. Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine (Phila Pa 1976) 1996;21:271-7.

34) Kang JD, Georgescu HI, McIntyre-Larkin L, et al. Herniated cervical intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine (Phila Pa 1976) 1995;20:2373-8.

35) Takahashi H. [A mechanism for sciatic pain caused by lumbar disc herniation--involvement of inflammatory cytokines with sciatic pain]. Nihon Seikeigeka Gakkai Zasshi 1995;69:17-29. (in Japanese)

36) O'Donnell JL, O'Donnell AL. Prostaglandin E2 content in herniated lumbar disc disease. Spine (Phila Pa 1976) 1996;21:1653-5. discussion 1655-6.

37) Willburger RE, Wittenberg RH. Prostaglandin release from lumbar disc and facet joint tissue. Spine (Phila Pa 1976) 1994;19:2068-70.

38) Kang JD, Stefanovic-Racic M, McIntyre LA, et al. Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine(Phila Pa 1976)1997;22:1065-73.

39) Kang SM, Schneider DB, Lin Z, et al. Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med 1997;3:738-43.

40) Seguin CA, Pilliar RM, Roughley PJ, et al. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine 2005;30:1940-8.

41) Gruber HE, Hoelscher GL, Ingram JA, et al. Production and expression of RANTES (CCL5) by human disc cells and modulation by IL-1-beta and TNF-alpha in 3D culture. Expe Mol Pathol 2014;96:133-8.

42) Kepler CK, Markova DZ, Dibra F, et al. Expression and Relationship of Proinflammatory Chemokine RANTES/CCL5 and Cytokine IL-1beta in Painful Human Intervertebral Discs. Spine (Phila Pa 1976) 2013;38:873-80.

43) Guptarak J, Wanchoo S, Durham-Lee J, et al. Inhibition of IL-6 signaling:A novel therapeutic approach to treating spinal cord injury pain. Pain 2013;154:1115-28.

44) Murakami T, Kanchiku T, Suzuki H, et al. Anti-interleukin-6 receptor antibody reduces neuropathic pain following spinal cord injury in mice. Exp Ther Medi 2013;6:1194-8.

45) Zhou YQ, Liu Z, Liu ZH, et al. Interleukin-6:an emerging regulator of pathological pain. J Neuroinflammation 2016;13:141. PubMed PMID:27267059.

46) Kunori S, Matsumura S, Okuda-Ashitaka E, et al. A novel role of prostaglandin E2 in neuropathic pain:blockade of microglial migration in the spinal cord. Glia 2011;59:208-18．

47) St-Jacques B, Ma W. Role of prostaglandin E2 in the synthesis of the pro-inflammatory cytokine interleukin-6 in primary sensory neurons:an in vivo and in vitro study. J Neurochem 2011;118:841-54.

48) Ohtori S, Miyagi M, Eguchi Y, et al. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis:a prospective randomized study. Spine (Phila Pa 1976) 2012;37:439-44.

49) Genevay S, Finckh A, Zufferey P, et al Adalimumab in acute sciatica reduces the long-term need for surgery:a 3-year follow-up of a randomised double-blind placebo-controlled trial. Ann Rheum Dis 2012 71:560-2.

50) Okoro T, Tafazal SI, Longworth S, et al Tumor necrosis alpha-blocking agent (etanercept):a triple blind randomized controlled trial of its use in treatment of sciatica. J Spinal Disord Tech 2010;23:74-7.

51) Genevay S, Viatte S, Finckh A, et al Adalimumab in severe and acute sciatica:a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:2339-46.

52) Ohtori S, Miyagi M, Eguchi Y, et al. Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica. Eur Spine J 2012;21:2079-84.

53) Genevay S, Stingelin S, Gabay C. Efficacy of etanercept in the treatment of acute, severe sciatica:a pilot study. Ann Rheum Dis 2004;63:1120-3.

54) Korhonen T, Karppinen J, Paimela L, et al. The treatment of disc-herniation-induced sciatica with infliximab:one-year follow-up results of FIRST II, a randomized controlled trial. Spine (Phila Pa 1976) 2006;31:2759-66.

55) Cohen SP, White RL, Kurihara C, SR, et al. Epidural steroids, etanercept, or saline in subacute sciatica:a multicenter, randomized trial. An Inter Med 2012;156:551-9.

56) Wang YF, Chen PY, Chang W, et al. Clinical significance of tumor necrosis factor-alpha inhibitors in the treatment of sciatica:a systematic review and meta-analysis. PloS One 2014;9:e103147.