류마티스관절염 활막세포에서 IL-17과 TLR 상호전달을 통한 RANKL과 IL-6 생성 조절 = IL-17 and Toll-Like Receptor 2 or Toll-Like Receptor 4 Combined Engagement Upregulates RANKL and IL-6 in Human Rheumatoid Synovial Fibroblasts

다국어 초록 (Multilingual Abstract)

Objective: The aim of this study was to clarify whether stimulation of recombinant IL-17, TLR2 and TLR4 by their specific ligands induces the production of RANKL and IL-6 in the fibroblast-like synoviocytes (FLSs) from RA patients. Methods: FLSs were isolated from RA synovial tissues and they were stimulated with the IL-17, TLR2 ligand bacterial peptidoglycan (PGN) and TLR4 ligand lipopolysaccharide (LPS). The RANKL levels were assessed by RT-PCR and western blotting. The expressions of IL-17, TLR2, TLR4, RANKL and IL-6 in the RA synovium were quantified by immunohistochemistry and these values were compared with the values obtained in the osteoarthritis synovium. The increased IL-6 production in the culture supernatants of the RA FLSs was quantified by sandwich ELISA. Results: The mRNA and protein levels of RANKL and IL-6 increased in the RA FLSs stimulated with PGN, LPS and IL-17, or PGN plus IL-17 or LPS plus IL-17. The expressions of IL-17, TLR2, TLR4, RANKL and IL-6 were much higher in the RA synovium than those in the osteoarthritis (OA) synovium. Conclusion: We observed synergistic effects of TLR-2, TLR-4 and IL-17 upon the induction of RANKL. In conclusion, our data supports the previous evidence of an important role of TLR-2, TLR-4 and IL-17 in the pathogenesis of RA.

참고문헌 (Reference)

1 Mangan PR, "Transforming growth factor-beta induces development of the T (H)17 lineage" 441 : 231-234, 2006

2 Brentano F, "The role of Toll-like receptor signalling in the pathogenesis of arthritis" 203 : 90-96, 2005

3 Toh ML, "The role of T cells in rheumatoid arthritis: new subsets and new targets" 19 : 284-288, 2007

4 Haynes DR, "The osteoclastogenic molecules RANKL and RANK are associated with periprosthetic osteolysis" 83 : 902-911, 2001

5 Sato K, "Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction" 203 : 2673-2682, 2006

6 Tamura T, "Soluble interleukin-6 receptor triggers osteoclast formation by interleukin-6" 90 : 11924-11928, 1993

7 Madhok R, "Serum interleukin 6 levels in rheumatoid arthritis:correlations with clinical and laboratory indices of disease activity" 52 : 232-234, 1993

8 Madhok R, "Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity" 52 : 232-234, 1993

9 Bettelli E, "Reciprocal developmental pathways for the generation of pathogenic effector TH17 andregulatory T cells" 441 : 235-238, 2006

10 Nakashima T, "Protein expression and functional difference of modulation of the expression by osteotropic factors and cytokines" 275 : 768-775, 2000

11 Cai L, "Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo" 16 : 10-21, 2001

12 Kong YY, "OPGL is a key regulator of osteoclastogenesis, lympocyte development and lymphnode organogenesis" 397 : 315-323, 1999

13 McFarland HF, "Multiple sclerosis: acomplicated picture of autoimmunity" 8 : 913-919, 2007

14 Sack U, "Interleukin-6 in synovial fluid is closely associated with chronic synovitis in rheumatoid arthritis" 13 : 45-51, 1993

15 Kudo O, "Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL independent mechanism" 32 : 1-7, 2003

16 Aggarwal S, "Interleukin-23 promotes a distinct CD4T cell activation state characterized by the production of interleukin-17" 278 : 1910-1914, 2003

17 Attur MG, "Interleukin-17 up-regulation of nitric oxide production in human osteoarthritis cartilage" 40 : 1050-1053, 1997

18 Chevrel G, "Interleukin-17 increases the effects of IL-1 beta on muscle cells: arguments for the role of T cells in the pathogenesis of myositis" 137 : 125-133, 2003

19 Miossec P, "Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy" 48 : 594-601, 2003

20 LeGrand A, "Interleukin-1, tumor necrosis factor a, and Interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci" 44 : 2078-2083, 2001

21 Lee JH, "Interleukin 17 (IL-17) Increases the Expression of Toll-like Receptor-2, 4, and 9 by Increasing IL-1β and IL-6 Production in Autoimmune Arthritis" 36 : 684-692, 2009

22 Nishimoto N, "Inhibition of IL-6 for the treatment of inflammatory diseases" 4 : 386-391, 2004

23 Kurihara N, "IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release" 144 : 4226-4230, 1990

24 Fantini MC, "IL-21 regulates experimental colitis by modulating the balance between T (reg) and Th17 cells" 37 : 3155-3163, 2007

25 Hwang SY, "IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB- and PI3-kinase/Akt-dependent pathways" 6 : R120-R128, 2004

26 Kotake S, "IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis" 103 : 1345-1352, 1999

27 Kim KW, "Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation" 110 : 54-64, 2007

28 Chabaud M, "Human interleukin-17: a T cellderivedproinflammatory cytokine produced by the rheumatoid synovium" 42 : 963-970, 1999

29 Seibl R, "Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium" 162 : 1221-1227, 2003

30 Lacey D, "Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor" 48 : 103-109, 2003

31 Chole RA, "Cellular and subcellular events of bone resorption in human and experimental cholesteatoma: The role of osteoclasts" 94 : 76-95, 1984

32 Page G, "Anatomic localization of immature and mature dendritic cell subsets in dermatomyositis and polymyositis" 50 : 199-208, 2004

33 Miossec P, "An update on the cytokine network in rheumatoid arthritis" 16 : 218-222, 2004

34 Takahashi N, "A new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function" 256 : 449-455, 1999