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AB0097 IL-6 blockade enhances the therapeutic effect of steroids
  1. M. Suzuki,
  2. M. Shiina,
  3. H. Yoshida,
  4. M. Hashizume,
  5. K. Tanaka,
  6. M. Mihara
  1. Product Research Dept., Chugai Pharmaceutical Co., Gotemba, Japan

Abstract

Background Steroids are commonly used for the treatment of chronic inflammatory diseases. Although the anti-inflammatory effects of steroids are to be expected, the prevalence of side-effects caused by high dosages of steroids is also high. Therefore, it is very important to taper the dosage of steroids. However, patients with chronic inflammatory disease sometimes develop a resistance to therapy with steroids, resulting in high dosages of steroids. Because elevated levels of IL-6 are found in these patients, it is thought that IL-6 might directly induce steroid-resistance.

Objectives We examined whether IL-6 attenuates the anti-inflammatory effect of steroids in vivo and in vitro.

Methods 1) To prepare a collagen-induced arthritis (CIA) model, DBA/1J mice were immunized with bovine type II collagen, and 21 days later (Day 21) given once again a booster injection. Prednisolone (PSL) was intraperitoneally administered at doses of 1, 3, and 6 mg/kg five times a week from Day 21. Rat anti-mouse IL-6R monoclonal antibody (MR16-1) was intraperitoneally administered once on Day 21. Clinical symptoms of arthritis were evaluated by observation and expressed as an arthritis score on a scale of 0–4 for each limb.

2) THP-1 macrophages were pretreated with 100 ng/mL of IL-6 or culture medium for 24 h. After medium replacement, cells were stimulated by lipopolysaccharide (LPS) in the presence or absence of 1 μM of dexamethasone (DEX) for another 3 h. After culture, to evaluate the inflammatory response, expression levels of CCL20 mRNA were determined by RT-PCR. Moreover, the influence of IL-6 on DEX-induced nuclear translocation of glucocorticoid receptor (GR) was examined by immunostaining and western blotting of GR.

Results PSL dose-dependently reduced arthritis score in the CIA model on Day 33 (PSL 1 mg/kg: 72% of control; PSL 3 mg/kg: 51%; PSL 6 mg/kg: 21%). MR16-1 in combination with low doses of PSL improved clinical symptoms significantly better than the same dose of PSL alone on Day 33 (PSL 1 mg/kg: 43% of control; PSL 3 mg/kg: 25%), even though administration of MR16-1 alone resulted in no improvement. On the other hand, no significant difference in arthritis score was found between PSL 6 mg/kg alone and in combination with MR16-1 on Day 33 (PSL 6 mg/kg: 21% of control; PLS 6 mg/kg plus MR16-1: 17%). Interestingly, however, the combination of PSL 6 mg/kg and MR16-1 reduced symptoms significantly better than PSL 6 mg/kg alone in the later periods from Day 38 to Day 50. To explore how MR16-1 could improve the anti-inflammatory effect of PSL, we next examined the influence of IL-6 on DEX activity, which suppresses the LPS-mediated inflammatory response in macrophages. The increased expression of CCL20 induced by LPS was clearly suppressed by DEX, but IL-6 pretreatment attenuated the inhibitory effect of DEX. Furthermore, IL-6 pretreatment decreased GR expression and inhibited GR nuclear translocation.

Conclusions We demonstrated that IL-6 blockade enhanced the therapeutic effect of steroids, possibly through restoring GR expression and nuclear translocation of GR repressed by IL-6. It might be possible to taper the dosage of steroids by IL-6 blockade.

Disclosure of Interest None Declared

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