IL-15에 의한 류마티스관절염 환자 활막 섬유모세포에서의 SDF-1 유도 = IL-15 Induced an Increased SDF-1 Expression in the Synovial Fibroblasts of Patients with Rheumatoid Arthritis

다국어 초록 (Multilingual Abstract)

Objective: Interleukin-15 (IL-15) recruits and activates synovial T cells, and IL-15 plays an important role in amplifying and perpetuating inflammation in the pathogenesis of rheumatoid arthritis (RA). Stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for memory T cells in the inflamed RA synovium. This study investigated the effect of IL-15 on SDF-1 production in RA fibroblast-like synoviocytes (FLS). Methods: The expressions of IL-15 and SDF-1 were determined from the synovium of patients with RA and osteoarthritis (OA) by performing immunohistochemistry. The expressions of SDF-1 was measured from the RA FLS that were cultured with IL-15 and IL-17 by real-time RT-PCR and ELISA. The SDF-1 expression was also measured, via ELISA, from the RA FLS stimulated by IL-15 together with the inhibitors of such intracellular signal molecules as phosphatidylinositol 3-kinase (PI 3-kinase, LY294002), STAT3 (AG490), MAP Kinase (PD98059), NF-κB (parthenolide) and activator protein 1 (AP-1, curcumin). Results: IL-15 and SDF-1 were mainly expressed in the RA synovium compared to that of the OA synovium. IL-15 increased the SDF-1 expressions and it, and had an additive effect with IL-17 on the SDF-1 expressions in the cultured RA FLS. The IL-15 induced increase of the SDF-1 expression in the cultured RA FLS was blocked by the inhibitors of PI 3-kinase, NF-κB and AP-1. Conclusion: The SDF-1 expression was increased in the RA synovium and it was up-regulated by IL-15 in the RA FLS through the PI 3-kinase, NF-κB, and AP-1 pathways. These results imply that the IL-15 induced increase of the SDF-1 expressions may be involved in the immunopathogenesis of RA.

참고문헌 (Reference)

1 Kim KW, "Up-regulation of stromal cell-derived factor 1 (CXCL12) production in rheumatoid synovial fibroblasts through interactions with T lymphocytes: role of interleukin-17 and CD40L-CD40 interaction" 56 : 1076-1086, 2007

2 McInnes IB, "The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis" 2 : 175-182, 1996

3 Baslund B, "Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-ofconcept study" 52 : 2686-2692, 2005

4 Ferrari-Lacraz S, "Targeting IL-15 receptorbearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis" 173 : 5818-5826, 2004

5 Pablos JL, "Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis" 170 : 2147-2152, 2003

6 Ernestam S, "Synovial expression of IL-15 in rheumatoid arthritis is not influenced by blockade of tumour necrosis factor" 8 : R18-, 2006

7 Mittal GA, "Stromal cellderived factor-1 alpha in rheumatoid arthritis" 42 : 915-916, 2003

8 Nanki T, "Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium" 165 : 6590-6598, 2000

9 Kanbe K, "Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4" 46 : 130-137, 2002

10 Groh V, "Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis" 100 : 9452-9457, 2003

11 Ruchatz H, "Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immuno pathology" 160 : 5654-5660, 1998

12 De Klerck B, "Pro-inflammatory properties of stromal cellderived factor-1 (CXCL12) in collagen-induced arthritis" 7 : R1208-R1220, 2005

13 Muller-Landner U, "Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis" 1 : 102-110, 2005

14 Waldmann T, "Interleukin-2, interleukin-15, and their receptors" 16 : 205-226, 1998

15 Oppenheimer-Marks N, "Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells in vitro and in the SCID mouse-human rheumatoid arthritis model in vivo" 101 : 1261-1272, 1998

16 Thurkow EW, "Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis" 181 : 444-450, 1997

17 Tamamura H, "Identification of a CXCR4 antagonist, a T140 analog, as an anti-rheumatoid arthritis agent" 569 : 99-104, 2004

18 Giri JG, "Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor" 14 : 3654-3663, 1995

19 Miranda-Carús ME, "IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate" 173 : 1463-1476, 2004

20 Hitchon C, "Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts" 46 : 2587-2597, 2002

21 Mbemba E, "Glycans and proteoglycans are involved in the interactions of human immunodeficiency virus type 1 envelope glycoprotein and of SDF-1α with membrane ligands of CD4+ CXCR4+ cells" 265 : 354-364, 1999

22 Cho ML, "Effector function of type II collagenstimulated T cells from rheumatoid arthritis patients: cross-talk between T cells and synovial fibroblasts" 50 : 776-784, 2004

23 Murdoch C, "CXCR4: chemokine receptor extraordinaire" 177 : 175-184, 2000

24 Burger JA, "CXCR4: a key receptor in the cross talk between tumor cells and their microenvironment" 107 : 1761-1767, 2006

25 Grassi F, "CXCL12 chemokine upregulates bone resorption and MMP-9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients" 199 : 244-251, 2004

26 Dubois-Laforgue D, "A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes" 50 : 1211-1213, 2001