Background Glucocorticoids (GCs) such as prednisolone (PSL) and dexamethasone (DEX) are the main therapies used for chronic inflammatory diseases. GCs are potent and effective, but induce many side-effects such as osteoporosis, making it important to reduce dose. Some patients have difficulty tapering off GCs because of GC resistance. In Rheumatoid arthritis (RA), about 30% of patients fail to show good response to GCs [1,2]. Pro-inflammatory cytokines such as IL-6 are reportedly involved in GC resistance . However, the influence of IL-6 inhibition on steroid action has not been fully examined.
Objectives To investigate with a mouse arthritis model whether IL-6 regulates both anti-inflammatory effects and side-effects of GCs.
Methods 1) A collagen-induced arthritis (CIA) model was used: mice were immunized intradermally with bovine type II collagen, and 21 days later (Day 21) were given a booster injection. From Day 21 mice were treated intraperitoneally with 3 or 6 mg/kg PSL five times a week (PSL3 group; PSL6 group) or 8 mg of anti-mouse IL-6R monoclonal antibody as an IL-6 inhibitor once on Day 21 (anti-IL-6R group). Other mice were given a combination of the two from Day 21 (PSL3+anti-IL-6R group; PSL6+anti-IL-6R group). Clinical symptoms of arthritis were evaluated by observation and expressed as a score of 0–4 for each limb. Lumbar vertebral BMD was measured with DXA to assess side effects of PSL.
2) Synovial cells from CIA mice and mouse osteoblastic cell line MC3T3-E1 were pretreated with 100 ng/mL of IL-6. After medium replacement, cells were stimulated by 1 μM of DEX for another 3 or 24 h. After culture, to evaluate inflammatory response in synovial cells, expression levels of cyclooxygenase (COX)-2 mRNA were examined by real-time PCR and the influence of IL-6 on DEX-induced nuclear translocation of glucocorticoid receptor (GR) were examined by western blotting. To evaluate osteogenic response in MC3T3-E1 cells, expression levels of osteocalcin (OC) mRNA were determined by real-time PCR.
Results 1) PSL dose-dependently reduced arthritis score in the CIA model on the peak of arthritis (Day 33). PSL3+anti-IL-6R improved clinical symptoms significantly more than PSL3 alone on Day 33 although anti-IL-6R alone was ineffective against swelling when administered on Day 21. A significant decrease in lumbar vertebra BMD by CIA was confirmed. Interestingly, PSL6 alone produced the same degree of arthritis improvement as PSL3+anti-IL-6R, but lumbar vertebral BMD was higher in the PSL3+anti-IL-6R group than in the PSL6 group.
2) To explore how anti-IL-6R could improve these effects of PSL, we examined the influence of IL-6 on DEX activity in vitro. COX-2 expression was clearly suppressed by DEX, but IL-6 pretreatment attenuated the inhibitory effect of DEX, and IL-6 pretreatment inhibited GR nuclear translocation in synovial cells. On the other hand, OC expression was suppressed by DEX, and IL-6 pretreatment enhanced this inhibitory effect of DEX in MC3T3-E1 cells.
Conclusions Anti-IL-6R augmented the anti-inflammatory effect of GCs via recovery of nuclear translocation of GR repressed by IL-6, and improved side-effects via a pathway independent of GR nuclear translocation. Anti-IL-6R might be a drug which makes GC tapering possible.
Scand J Rheumatol. 2007;36:167-71
Arthritis Rheum. 1995;38:334-42
Proc Natl Acad Sci U S A. 2012;109:5995-9
Disclosure of Interest None Declared
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