The roles of interleukin-16 and insulin-like growth factor-1 receptor in rheumatoid arthritis

• Main Authors: Chih-NengTsai, 蔡智能
• Other Authors: Ming-Fei Liu
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/35309472738912646098

碩士 === 國立成功大學 === 臨床醫學研究所 === 99 === Abstract Background: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis, which could result in joint destruction and deformity. Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), are highly involved in pathogenesis. Interleukin-16 (IL-16) could be secreted by CD4+ and CD8+ T lymphocytes, B lymphocytes, airway epithelium, mast cells and cytokine-activated fibroblasts and functions as a potent chemoattractant for T lymphocytes. IL-16 has been demonstrated in the synovial fluid of patients with active RA. Synovial fibroblasts from patients with RA could produce high levels of IL-16 in response to immunoglobulin G of RA (RA-IgG). This induction necessarily involves through the insulin-like growth factor-1 receptor (IGF-1R). Besides, IGF-1R is also expressed on T lymphocytes. This study is designed to evaluate the difference of IL-16 between RA and osteoarthritis (OA) patients and the correlation between IL-16 and disease status and other inflammatory cytokines in RA patients. The roles of IGF-1R in production of TNF-α by T lymphocytes and IL-6 or matrix metalloproteinase 3 (MMP3) by fibroblasts in RA patients would also be delineated. Methods: We checked the seral level of IL-16 with ELISA in 39 RA and 39 OA patients. IL-16 and disease status parameters of RA, such as erythrocyte sediment rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), tender joint count (TJC), swollen joint count (SJC) and DAS 28 in 30 patients were evaluated initially and 3 months later. The correlation coefficient of IL-16 and each disease parameter was disclosed with the cross-section and follow-up studies. The data of the first examination was adopted in the cross-section study and the difference of IL-16 or each parameter of disease status during the 3 months was analyzed in the follow-up study. We also checked TNF-α and disease parameters in 21 patients, and IL-6 and parameters of disease status in 15 patients. The correlations of TNF-α or IL-6 with disease activity were measured as that of IL-16. The correlation coefficients between difference of IL-16 and change of TNF-α or IL-6 were evaluated. Besides, the correlation of seral level of IL-16 and the binding optic density of IGF-1R and its antibody was also revealed. We collected T lymphocytes by flow cytometry and used sera of RA patients to stimulate T lymphocytes. Blocking monoclonal antibody against IGF-1R was used to evaluate the significance of IGF-1R in TNF-α production. The sera of RA patients were also used to stimulate fibroblasts to see if MMP3 or IL-6 expression could be up-regulated. In case of increased production of MMP3 or IL-6, blocking monoclonal antibody against IGF-1R or removal of seral antibody of IGF-1R would be used to evaluate if the process could be blocked. Results: The difference of seral IL-16 in 39 RA and 39 OA patients was not significant (P=0.799). In the cross-section study, IL-16 was not correlated with the disease parameters. The follow-up study revealed that the difference of IL-16 was still not correlated with change of ESR (r=0.185, P=0.328), CRP (r=0.206, P=0.274), RF (r=-0.129, P=0.496), TJC (r=0.226, P=0.221), SJC (r=0.068, P=0.715) and DAS 28 (r=0.237, P=0.208). In the cross-section and follow-up studies, TNF-α or IL-6 had no correlation with all the parameters of disease status. The difference of IL-16 was markedly correlated with change of TNF-α (r=0.712, P＜0.001) but not correlated with change of IL-6 (r=0.104; P=0.713). IL-16 had no correlation with the binding intensity of IGF-1R and its antibody (r=-1.21, P=0.621). After treatment with sera of RA patients, the levels of TNF-αby T lymphocytes isolated from RA patients were not decreased in the samples added with blocking monoclonal antibody against IGF-1R than those without loading of antibody. MMP3 production was not increased than baseline seral level after fibroblasts obtained from RA patients are added. The levels of IL-6 were markedly increased (P＜0.001) after fibroblasts were cultured with sera of RA patients. However, IL-6 production couldn’t be blocked with blocking monoclonal antibody against IGF-1R or removal of antibody against IGF-1R. Even removal of immunoglobulin G with protein A had no impact in production of IL-6. Conclusion: In our study, the seral levels of IL-16 are not different between 39 RA and 39 OA patients. In the cross-section and follow-up studies, IL-16, TNF-α and IL-6 are not correlated with all the disease parameters of RA, including ESR, CRP, RF, tender joint count, swollen joint count and DAS 28. IL-16 has markedly positive correlation with TNF-α but not IL-6. The association between IL-16 and TNF-α needs to be further studied. IGF-1R plays no role in production of TNF-α by T lymphocytes. The levels of MMP3 secreted from fibroblasts are not elevated after mixed with sera of RA patients. The levels of IL-6 are markedly increased after fibroblasts are cultured with sera of RA patients, but IGF-1R still plays no role. The increased production of IL-6 is even IgG-independent. Key words: rheumatoid arthritis, IL-16, TNF-α, IL-6, fibroblast, IGF-1R, MMP3, T lymphocyte