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Delayed resolution of acute inflammation during zymosan-induced arthritis in leptin-deficient mice


Proinflammatory or anti-inflammatory roles have been ascribed to leptin, depending on the experimental model investigated. We recently observed decreased severity of antigen-induced arthritis (AIA) in leptin-deficient ob/ob mice. However, joint inflammation in AIA depends on the immune response to an exogenous antigen, which is impaired in ob/ob mice.


The aim of the present study was to investigate potential effects of leptin in zymosan-induced arthritis (ZIA), a model of acute inflammatory arthritis, which is not dependent on the adaptive immune response.

Methods and results

Arthritis was induced in ob/ob and control +/? C57BL/6 mice by injection of zymosan A (Zy) into the knee joint cavity. Increased blood flow, reflecting the severity of joint inflammation, was quantified by uptake of technetium 99 m. It was similar 6 and 24 hours after Zy injection in ob/ob and control mice. However, it persisted on day 3 in ob/ob animals, while subsiding in controls. Histology repeatedly showed similar severity of arthritis in ob/ob mice and controls on day 3, but arthritis always tended to be more severe in ob/ob than in +/? mice at later time points (days 14 and 21). Similar observations were made using leptin-receptor-deficient db/db mice, suggesting that the effects of leptin are mediated via the Ob-Rb receptor. The acute-phase response was examined in ob/ob and control mice after injection of Zy by measuring circulating levels of interleukin (IL)-6 and serum amyloid A (SAA). Serum IL-6 increased in all animals during the first 24 hours after Zy injection, but IL-6 levels were significantly higher in ob/ob mice than in controls. SAA increased in all animals during the first 3 days after Zy injection, but SAA levels were significantly higher on days 1 and 3 in ob/ob animals than in controls. The acute-phase response thus appeared to be more pronounced in ob/ob mice, although corticosterone levels were significantly elevated in these animals at baseline and throughout the experiment


These data suggest that the resolution of acute inflammation during ZIA is delayed in leptin-deficient animals. In this model, leptin thus appears to display anti-inflammatory properties, limiting the acute phase response and the chronicity of arthritis.

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Bernotiene, E., Palmer, G., Talabot-Ayer, D. et al. Delayed resolution of acute inflammation during zymosan-induced arthritis in leptin-deficient mice. Arthritis Res Ther 5 (Suppl 1), 93 (2003).

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