Special aspects of interleukin-33 and the IL-33 receptor complex

Interleukin-33 (IL-33) is an unconventional member of the IL-1 family: it is a dual function cytokine. Many different cell types, tissue cells and leukocytes, produce IL-33 either constitutively or after stimulation and release it by a poorly defined molecular mechanism. Free IL-33 acts as a classical cytokine by binding to target cells expressing receptors for IL-33 minimally consisting of ST2 and IL-1RAcP. Depending on the target cell type IL-33 will stimulate cell-type specific signal transduction mechanisms and thereby change the biosynthetic profile of the respective cell. In addition, it is stored in the nucleus of cells and may be released after cell stress, death by injury or necrosis, acting as an alarmin by orchestrating a sterile inflammation. Furthermore, IL-33 has intracrine functions in the cell producing it, which are independent of IL-33 receptors. Intracellular IL-33 is predominantly found in the nucleus associated to the chromatin and may exert gene regulatory function by yet poorly defined mechanisms. It is the aim of this review to address two basic biological aspects of the IL-33/IL-33 receptor system. First, to summarize the current understanding of the fate and function of intracellular IL-33, and second, to discuss recent advances in the knowledge of the molecular composition, function and regulation of the IL-33 receptor complex, including initial signaling mechanisms.