Two pivotal aspects of the IL-33 system are characterized in this study: First the composition and function of the IL-33 receptor complex on IL-33 responder cells and second the generation of biologically active IL-33 by the IL-33 producer cell. IL-33 binds to the IL-33 receptor ?-chain (ST2) and as is shown here, this results in the recruitment of interleukin-1 receptor accessory protein (IL-1RAcP) as the co-receptor. The IL-33-dependent interaction of membrane bound and soluble form of IL-1RAcP and IL-33R?-chain was demonstrated in co-immunoprecipitation assays. Common notion in the field is that IL-33, like IL-1? and IL-18, requires processing by caspase-1 to a mature form, in order to achieve biological activity as a cytokine. Contrary to the current dogma, here it is described that IL-33 is biologically active as unprocessesed full length molecule. Full length IL-33 binds to the IL-33 receptor-? chain and mediates the recruitment of IL-1RAcP to activate cells. IL-33 is processed in cells, however not by caspase 1 to a mature, biologically active, IL-33 but instead it is cleaved by caspase 3 at aa175 to yield two products which are both unable to bind to the IL-33 receptor.

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