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THU0119 Anti-IL-6 Receptor Antibody is Effective in Treating Arthritis in Obese Mice
  1. M. Suzuki1,
  2. H. Yoshida1,
  3. Y. Matsumoto1
  1. 1Product Research Dept., Chugai Pharmaceutical Co., Gotemba, Japan

Abstract

Background It is reported that, compared with non-obese patients, obese Rheumatoid arthritis (RA) patients experience worsening of symptoms [1] and do not respond as well to TNF inhibitors [2, 3]. The main reason is thought to be that in obesity many adipokines such as IL-6 and TNF-α are produced from hypertrophied adipocytes and infiltrating macrophages, resulting in exacerbation of inflammation. However, the efficacy of IL-6 inhibition has not yet been fully examined.

Objectives The purpose of this study was to investigate the difference in response to IL-6 inhibition and to TNF inhibition in therapy for arthritis with obesity, using a mouse model of arthritis.

Methods 1) To prepare a collagen-induced arthritis (CIA) model, mice fed a normal diet (non-obese mice) and mice fed a high-fat diet (obese mice; relative body weight: 125%) were immunized intradermally with bovine type II collagen, and 21 days later (Day 21) once again given a booster injection. We used anti-IL-6 receptor antibody (anti-IL-6R) as an IL-6 inhibitor and TNFR-Fc as a TNF inhibitor. Anti-IL-6R was intraperitoneally administered at a dose of 8 mg twice (Day 0 and 21). TNFR-Fc was intraperitoneally administered at doses of 1 mg three times a week from Day 0. Clinical symptoms of arthritis were evaluated by observation and expressed as an arthritis score on a scale of 0–4 for each limb. IL-6, TNF-α, and macrophage marker F4/80 mRNA expressions in hind limbs of mice immediately before primary immunization were measured by real-time PCR.

2) The mouse macrophage cell line RAW264.7 was cultured with 10 ng/mL of IL-6 or TNF-α for 24 h. After culture, to evaluate the inflammatory response, expression levels of monocyte chemoattractant protein (MCP)-1 and cyclooxygenase (COX)-2 mRNA were determined by real-time PCR.

Results 1) Arthritis scores were relatively higher (but not significantly) in obese mice than in non-obese mice on the peak of arthritis (Day 33). Furthermore, the anti-arthritic effect of TNFR-Fc was lower in obese mice than in non-obese mice(inhibition ratio: 54% vs. 64%). Interestingly, the anti-arthritic effect of anti-IL-6R was higher in obese mice (inhibition ratio: 87% vs. 62%). Moreover, in non-arthritic control mice, the expression levels of IL-6, TNF-α and F4/80 were higher in hind limbs of obese mice than in non-obese mice.

2) To explore the roles of anti-IL-6R and TNFR-Fc, we next examined the influence of IL-6 or TNF-α activity in RAW264.7 cells. The expressions of MCP-1 and COX-2 were dramatically increased by IL-6 but not by TNF-α.

Conclusions We demonstrated that the anti-arthritis effect of TNFR-Fc was reduced by obesity, as is also shown in clinical reports, and that the anti-arthritis effect of anti-IL-6R was increased by obesity in this mouse model. One reason might be that obesity promotes macrophage infiltration and IL-6 is prominently involved in the inflammatory response of macrophages in mice. It goes without saying that it is essential for every patient to reduce excess weight because of its association with risk of developing other diseases such as cardiovascular disease and diabetes. However, anti-IL-6R has the potential to be useful in the treatment of all RA patients, even those who are obese.

References

  1. Arthritis Care Res (Hoboken). 2013; 94: 78-87

  2. Arthritis Rheum. 2011; 63: 359-64

  3. Arthritis Care Res (Hoboken). 2013; 94: 94-100

Disclosure of Interest None Declared

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