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FRI0365 Very-High-Concentration Leptin Suppresses Aggravation of Collagen Antibody-Induced Arthritis in Mice
  1. T. Okano1,
  2. T. Koike2,3,
  3. K. Inui1,
  4. M. Tada1,
  5. Y. Sugioka1,
  6. K. Mamoto1,
  7. H. Nakamura1
  1. 1Orthopaedic Surgery
  2. 2Center for Senile Degenerative Disorders, Osaka City University Graduate School of Medicine, Osaka
  3. 3Search Institute for Bone and Arthritis Disease, Shirahama Hamayu Hospital, Wakayama, Japan

Abstract

Background Leptin is an adipocytokine, produced mainly by adipocytes and controlling body weight through a hypothalamic relay activating the sympathetic nervous system. In rheumatoid arthritis (RA), a representative arthritis, serum leptin levels are reportedly higher in RA patients than in healthy controls, but negative results have also been reported. It is unclear whether serum leptin levels are rising as a pro-inflammatory cytokine with inflammation of RA or as an anti-inflammatory cytokine in an attempt by the body to suppress the inflammation already present.

Objectives We investigated the effects of very-high-concentration leptin on leptin transgenic (LepTg) mice in terms of cartilage destruction, bone destruction, joint synovitis and serum cytokine levels by using a mouse model of collagen antibody-induced arthritis (CAIA). We also examined effects on macrophages using high-concentration leptin for macrophage-like THP-1 cells in vitro.

Methods CAIA was induced for female age-matched 6- to 8-week-old C57BL/6J control mice, ob/ob mice and LepTg mice. Clinical evaluation of arthritis was monitored for 14 days and hindpaws were examined histologically. Serum cytokine levels were also analyzed on days 0 and 5. THP-1 cells were cultured and differentiated into macrophages and the effects of leptin on mRNA expression of interleukin (IL)-6 were examined by real-time quantitative PCR.

Results Serum leptin concentrations were approximately 20-fold higher in LepTg mice (133.1±33.3 ng/ml) than in control mice (7.2±0.5 ng/ml). Serum leptin levels in ob/ob mice were even lower (0.4±0.2 ng/ml). Limb joints showed marked swelling or redness in control mice. Conversely, evidence of arthritis was barely apparent in LepTg mice and ob/ob mice on day 9 (Fig. 1A). Clinical score was also low in LepTg mice and ob/ob mice (day 9: control, 10.5±4.2; LepTg, 3.8±1.2; ob/ob, 4.2±2.3) (Fig. 1B).Modified Mankin's histological scores for cartilage after arthritis were significantly higher in control mice (10.0±1.9) than in LepTg mice (1.3±1.0; P<0.05) and ob/ob mice (2.0±1.0; P<0.05) (Fig. 1C). Serum cytokine levels of IL-1β, IL-17, IL-10 and TNFα did not show any significant changes in any of the three groups from day 0 to 5. IL-6 level was higher in control mice than in LepTg and ob/ob mice on day 5. Moreover, elevation of IL-6 following lipopolysaccharide exposure in THP-1 cells was suppressed with high leptin concentrations in vitro. Very high concentrations of leptin may thus plausibly suppress IL-6 responses and progression of joint inflammation.

Conclusions Our current findings have identified a previously undescribed function of very high serum concentrations of leptin in suppressing IL-6 expression and autoimmune arthritis. Further studies are needed to determine whether high-concentration leptin injections may exert any therapeutic effects in CAIA, which may have important implications for the development of new strategies for treating patients with RA and other autoimmune diseases.

References

  1. Wisłowska M, Rok M, Jaszczyk B, Stepień K, Cicha M: Serum leptin in rheumatoid arthritis. Rheumatol Int. 2007;27(10):947-54.

  2. Sugioka Y, Tada M, Okano T, Nakamura H, Koike T: Acquired leptin resistance by high-fat feeding reduces inflammation from collagen antibody-induced arthritis in mice. Clin Exp Rheumatol. 2012;30(5):707-13.

Disclosure of Interest T. Okano: None declared, T. Koike Grant/research support: Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical, Eisai, Abbott Japan, Teijin Pharma, Banyu Pharmaceutical and Ono Pharmaceutical, Speakers bureau: Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical, Eisai, Abbott Japan, Teijin Pharma, Banyu Pharmaceutical and Ono PharmaceuticalM, K. Inui Grant/research support: Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Abbvie GK, Eisai Co.,Ltd., MSD K.K, Speakers bureau: Bristol-Myers K.K., Takeda Pharmaceutical Corporation, Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Abbvie GK, Astellas Pharma Inc, M. Tada: None declared, Y. Sugioka: None declared, K. Mamoto: None declared, H. Nakamura Grant/research support: Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Nippon Zoki Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Takeda Pharmaceutical Co., Ltd., Hisamitsu Pharmaceutical Co.,Inc., Ono Pharmaceutical Co., Ltd., Osteopharma Inc., Teijin Pharma Ltd., Asahi Kasei Pharma Co, Speakers bureau: Eisai Co.,Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Asahi Kasei Pharma Co., Teijin Pharma Ltd., Astellas Pharma Inc., Pfizer Japan Inc., Nippon Zoki Pharmaceutical Co., Ltd., Hisamitsu Pharmaceutical Co.,Inc., Janssen Pharmaceutical K.K

DOI 10.1136/annrheumdis-2014-eular.1945

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