Human adipose tissue is an important novel source of IL-1Ra: a new connection between immuno-inflammatory diseases and lipid metabolism

The increased production of IL-1, tumor necrosis factor (TNF)-α and IL-6 is implicated in the pathogenesis of various immuno-inflammatory diseases (i.e. rheumatoid arthritis), often accompanied by metabolic and cardiovascular complications. Cachexia and obesity may accompany these diseases, and IL-1, TNF-α, IL-6 are said to be increased in white adipose tissue (WAT). Fewer studies devolve on counter-regulatory mechanisms by cytokine inhibitors. Sera of obese patients showed a more than sevenfold increase in IL-1 receptor antagonist (IL-1Ra), which matches levels present in inflammatory autoimmune diseases and sepsis, and correlating with body mass index and insulin resistance. Subcutaneous and visceral human WAT of obese patients contained 0.4 and 0.7 ng IL-1Ra/mg protein, respectively. Thus, in an obese individual weighing 120 kg with 50% body fat, the 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 increased IL-1β – argues for an anti-inflammatory, compensating, mechanism associated with obesity. Our experiments with human WAT explants showed a strong stimulatory effect of phorbol myristate acetate and, more importantly, of IFN-β (as much as fivefold to 10-fold). Since the latter is considered a fibroblast-derived IFN, it is tempting to speculate that stromal cells and adipocytes might be part of a paracrine mechanism regulating 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-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 immune disease.