臨床整形外科46巻8号

2011年08月発行

境界領域/知っておきたい

インターロイキン23

著者： 森幹士¹

所属機関： ¹滋賀医科大学整形外科

ページ範囲：P.718 - P.722

はじめに

　免疫応答において，抗原により活性化されたCD4＋ナイーブT細胞は増殖しながら機能発現に向けた分化を開始する．その際には，どのようなサイトカイン環境にあるかによってその分化の方向性が決まるが，2種類のヘルパーT(Th)細胞(Th1/Th2細胞)に分化すると考えられていた．Th1細胞は細胞性免疫に，Th2細胞は液性免疫や感染防御に関わり，Th1/Th2バランスの破綻が様々な疾患の病態形成に関与すると理解され，T細胞が関わる病態はTh1，Th2のみで説明が可能であるような錯覚に陥っていた．ところが，2000年にTh1にもTh2にも属さない新しいサブセットであるTh17の存在が明らかとなった¹⁰⁾．この新しいサブセットが産生するインターロイキン(interleukin：IL)17やIL22などのサイトカインは，細胞外微生物(細菌)に対する感染防御やアレルギーや自己免疫性の炎症性疾患の病態に重要な役割を果たすことが明らかとなり注目を集めている(図1)．このTh17細胞の増殖と維持に深く関わるのがIL23であり²²⁾，種々の自己免疫疾患と関連が注目されている²⁵⁾．本稿では，このIL23と関節リウマチ(RA)をはじめとする整形外科関連疾患との関わりについて概説する．

参考文献

1) Cargill M, Schrodi SJ, Chang M, et al:A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273-290, 2007

2) Chabaud M, Durand JM, Buchs N, et al:Human interleukin-17:A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963-970, 1999

3) Chen L, Wei XQ, Evans B, et al:IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. Eur J Immunol 38:2845-2854, 2008

4) Cua DJ, Sherlock J, Chen Y, et al:Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744-748, 2003

5) Davidson SI, Wu X, Liu Y, et al:Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum 60:3263-3268, 2009

6) Dubinsky MC, Wang D, Picornell Y, et al:IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease. Inflamm Bowel Dis 13:511-515, 2007

7) Duerr RH, Taylor KD, Brant SR, et al:A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461-1463, 2006

8) Fujino S, Andoh A, Bamba S, et al:Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52:65-70, 2003

9) Gottlieb A, Menter A, Mendelsohn A, et al:Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis:randomised, double-blind, placebo-controlled, crossover trial. Lancet 373:633-640, 2009

10) Infante-Duarte C, Horton HF, Byrne MC, et al:Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 165:6107-6115, 2000

11) Iwakura Y, Ishigame H:The IL-23/IL-17 axis in inflammation. J Clin Invest 116:1218-1222, 2006

12) Kageyama Y, Kobayashi H, Kato N:Infliximab treatment reduces the serum levels of interleukin-23 in patients with rheumatoid arthritis. Mod Rheumatol 19:657-662, 2009

13) Karaderi T, Harvey D, Farrar C, et al:Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series. Rheumatology (Oxford) 48:386-389, 2009

14) Kim HR, Cho ML, Kim KW, et al:Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase-, NF-kappaB- and p38 MAPK-dependent signalling pathways. Rheumatology (Oxford) 46:57-64, 2007

15) Kim HR, Kim HS, Park MK, et al:The clinical role of IL-23p19 in patients with rheumatoid arthritis. Scand J Rheumatol 36:259-264, 2007

16) Kotake S, Udagawa N, Takahashi N, et al:IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103:1345-1352, 1999

17) Kurasawa K, Hirose K, Sano H, et al:Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463, 2000

18) Lee E, Trepicchio WL, Oestreicher JL, et al:Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 199:125-130, 2004

19) Leonardi CL, Kimball AB, Papp KA, et al:Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis:76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665-1674, 2008

20) Lew W, Chang JY, Jung JY, et al:Increased expression of interleukin-23 p19 mRNA in erythema nodosum-like lesions of Behçet's disease. Br J Dermatol 158:505-511, 2008

21) Lowes MA, Kikuchi T, Fuentes-Duculan J, et al:Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 128:1207-1211, 2008

22) Ma CS, Chew GY, Simpson N, et al:Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 205:1551-1557, 2008

23) Oppmann B, Lesley R, Blom B, et al:Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715-725, 2000

24) Papp KA, Langley RG, Lebwohl M, et al:Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis:52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371:1675-1684, 2008

25) Paradowska-Gorycka A, Grzybowska-Kowalczyk A, Wojtecka-Lukasik E, et al:IL-23 in the pathogenesis of rheumatoid arthritis. Scand J Immunol 71:134-145, 2010

26) Pimentel-Santos FM, Ligeiro D, Matos M, et al:Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population. Clin Exp Rheumatol 27:800-806, 2009

27) Rahman P, Inman RD, Gladman DD, et al:Association of interleukin-23 receptor variants with ankylosing spondylitis. Arthritis Rheum 58:1020-1025, 2008

28) Rueda B, Orozco G, Raya E, et al:The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann Rheum Dis 67:1451-1454, 2008

29) Sandborn WJ, Feagan BG, Fedorak RN, et al:A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 135:1130-1141, 2008

30) Sato K, Suematsu A, Okamoto K, et al:Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203:2673-2682, 2006

31) Singh R, Aggarwal A, Misra R:Th1/Th17 cytokine profiles in patients with reactive arthritis/undifferentiated spondyloarthropathy. J Rheumatol 34:2285-2290, 2007

32) Sung IH, Kim TH, Bang SY, et al:IL-23R polymorphisms in patients with ankylosing spondylitis in Korea. J Rheumatol 36:1003-1005, 2009

33) Teunissen MB, Koomen CW, de Waal Malefyt R, et al:Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 111:645-649, 1998

34) Yamazaki K, Onouchi Y, Takazoe M, et al:Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients. J Hum Genet 52:575-583, 2007

35) Yen D, Cheung J, Scheerens H, et al:IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310-1316, 2006

36) Wang X, Lin Z, Wei Q, et al:Expression of IL-23 and IL-17 and effect of IL-23 on IL-17 production in ankylosing spondylitis. Rheumatol Int 29:1343-1347, 2009

37) Wellcome Trust Case Control Consortium;Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, et al:Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329-1337, 2007

38) Wendling D, Cedoz JP, Racadot E, et al:Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. Joint Bone Spine 74:304-305, 2007

39) Wendling D:Interleukin 23:a key cytokine in chronic inflammatory disease. Joint Bone Spine 75:517-519, 2008

40) Wendling D, Cedoz JP, Racadot E:Serum and synovial fluid levels of p40 IL12/23 in spondyloarthropathy patients. Clin Rheumatol 28:187-190, 2009

41) Wong CK, Ho CY, Li EK, et al:Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 9:589-593, 2000