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Human adipose tissue: an important novel source of IL-1Ra

The increased production of proinflammatory IL-1, TNF-α and IL-6 is part of the pathogenesis of various immunoinflammatory diseases, often accompanied by metabolic and cardiovascular complications. Cachexia and obesity have been shown to accompany these diseases, and the cytokines IL-1, TNF-α, IL-6 are said to be increased in white adipose tissue (WAT). Few studies have been conducted to examine counter-regulatory mechanisms of cytokine inhibitors. Sera of obese patients showed a more than sevenfold increase in IL-1Ra, which matches levels present in inflammatory autoimmune diseases and sepsis, and correlates with body mass index and insulin resistance. Subcutaneous and visceral human WAT of obese patients contained 0.4 and 0.7 ng of IL-1Ra/mg protein, respectively. Thus, in an obese individual weighing 120 kg with 50% body fat, total WAT is estimated to contain 0.6 mg IL-1Ra protein (i.e. 200 times the amount of IL-1Ra in total serum), thus representing one of the main sources of IL-1Ra production. The increased IL-1Ra expression – not associated with an increase in IL-1β – argues for an anti-inflammatory, compensating mechanism associated with obesity. Our experiments with human WAT explants showed a strong stimulatory effect of PMA and, more importantly, of IFN-β (as much as 5- to 10-fold). Because the latter is a fibroblast-derived IFN, it is tempting to speculate that stromal cells and adipocytes might be part of a paracrine mechanism that regulates IL-1Ra secretion. In fact, newly formed adipose tissue is often found close to inflammatory lesions (i.e. synovial tissue). The functional consequences of the increased production of IL-1Ra by adipose tissue may represent an important counter-regulatory mechanism to inflammation at the local level. Furthermore, IL-1RI and IL-1 IL-1RAcP were also expressed in human WAT. Thus, substances that increase the production ratio of IL-1Ra/IL-1β by adipose tissue might serve as a novel target for therapeutic strategies in human immunoinflammatory diseases.

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Dayer, JM., Meier, C. Human adipose tissue: an important novel source of IL-1Ra. Arthritis Res Ther 6 (Suppl 1), 29 (2004).

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