Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1 - PubMed (original) (raw)
Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1
Marije I Koenders et al. Am J Pathol. 2005 Jul.
Abstract
Rheumatoid arthritis is characterized by an intermittent course of disease with alternate periods of remission and relapse. T cells, and in particular the T-cell cytokine interleukin-17 (IL-17), are expected to be involved in arthritic flares. Here, we report that neutralizing endogenous IL-17 during reactivation of antigen-induced arthritis prevents joint inflammation and bone erosion. Synovial IL-17 mRNA expression was clearly up-regulated during primary arthritis and was further enhanced after antigen rechallenge. Neutralization of IL-17 significantly prevented joint swelling at day 1 of flare and significantly suppressed joint inflammation and cartilage proteoglycan depletion at day 4, as assessed by histology. Blocking IL-17 also clearly reduced bone erosions. Cathepsin K, a marker of osteoclast-like activity, and synovial RANKL mRNA expression were both suppressed. The degree of bone erosions strongly correlated with the severity of joint inflammation, suggesting that anti-IL-17 treatment reduced bone erosion by suppressing joint inflammation. Interestingly, blocking IL-17 suppressed synovial expression of both IL-1beta and tumor necrosis factor-alpha, whereas blocking IL-1 did not affect tumor necrosis factor-alpha levels. These data indicate that IL-17 is an important upstream mediator in joint pathology during flare-up of experimental arthritis.
Figures
Figure 1
Up-regulation of IL-17 mRNA (A) and protein (B) levels in synovium from arthritic C57Bl/6 mice during AIA. At various time points during primary AIA and flare-up, synovium biopsies were taken for QPCR analysis, and synovial washouts were collected for protein determination. ΔΔCT-value, the mRNA expression corrected for GAPDH and compared with naive mice (day 0). Labels on top of the bars mention the fold mRNA increase compared with naive mice. The QPCR results are the average mRNA expression of two groups, consisting of six pooled synovium biopsies, measured in duplicate. The protein data show the mean with its SEM of three to eight animals per group.
Figure 2
Histopathological effects of anti-IL-17 treatment during flare-up of antigen-induced arthritis. Blocking of IL-17 during flare-up of arthritis results in suppressed joint swelling (A), influx of proinflammatory cells (B), and cartilage PG depletion (C). D: Histological sections representative for our arbitrary scoring system for infiltrate and cartilage PG depletion (0–3). Joint swelling was measured by 99mTc uptake at day 1 of flare-up, and total knee joints were isolated at day 4 for histological analysis. Results are the mean of at least nine mice per group; *P < 0.05; **P < 0.005 versus control-treated group, by Mann Whitney _U_-test. Histological sections for infiltrate stained with H&E and for cartilage PG depletion stained with safranin O. P, patella; F, femur; S, synovitis; GP, growth plate; C, cartilage; JS, joint space (Original magnification, ×50 or ×100).
Figure 3
Effect of anti-IL-17 treatment on bone erosion during flare-up of antigen-induced arthritis. Histological analysis at day 4 of flare-up shows that anti-IL-17 treatment reduces bone erosion in different parts of the murine knee joint (A) and that bone erosion is strongly correlated with the degree of joint inflammation (B). One group of mice was not flared to obtain background levels of joint pathology before flare-up of arthritis. P, patella; LF, lateral femur; MF, medial femur; Lig, ligament zone; LT, lateral tibia; MT, medial tibia. Results are the mean ± SEM of at least nine mice per group; *P < 0.01; **P < 0.005 versus control-treated group, by Mann Whitney _U_-test. Spearman R as calculated to determine the correlation between joint inflammation and bone erosion.
Figure 4
Anti-IL-17 treatment during flare-up of experimental arthritis reduces cathepsin K staining as a marker for osteoclast-like activity. Arthritic mice were treated with control rabbit antibodies (A) or anti-IL-17 antibodies (B), and total knee joints were isolated at day 4 for histological analysis. F, femur; C, cartilage; S, synovium. Original magnification, ×100 and ×200. Pictures are representative of immunostainings on several joint sections of both groups.
Figure 5
Neutralizing IL-17 or IL-1 during flare-up of arthritis reduces the levels of cytokines and chemokines in synovial washouts of arthritic mice. At various times after flare-induction, synovial washouts were collected and subsequently analyzed for cytokine and chemokine levels; IL-1β at 90 minutes and day 1 of flare-up (A); TNF-α at 90 minutes (B), and KCs at day 1 (C). Arthritic mice were treated with anti-IL-17, anti-IL-1, or control antibodies. One group of mice was not flared to obtain background expression levels before flare-up of arthritis. Results are the mean of five samples per group (n = 3 for background); *P < 0.05; **P < 0.01 versus control-treated group, by Mann Whitney _U_-test.
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