IL-33 was independently described by three different research groups interested in distinct biological topics. Onda et al. identified DVS27 as a protein that is upregulated in vasospastic cerebral arteries.1 Baekkevold et al. identified NF-HEV as a nuclear factor in the endothelial cells of high endothelial venules.2 Schmitz et al. identified IL-33 as an interleukin-1 family cytokine.3 DVS27, NF-HEV, and IL-33 all refer to the same multi-functional protein that is expressed primarily by endothelial and smooth muscle cells in the vasculature and airway.3, 4 IL-33 is upregulated by inflammatory stimulation in these cells, as well as keratinocytes and dermal fibroblasts, and by mechanical strain in cardiac fibroblasts.1, 5, 6
IL-33 is synthesized as a 270 amino acid protein in humans and contains an N-terminal nuclear localization signal (NLS), a helix-turn-helix (HTH) motif, and a C-terminal region with structural homology to IL-1 family cytokines. It can be cleaved in vitro by caspase-1 to generate an 18 kDa C-terminal fragment, which serves as a cytokine.3, 5 The fate of the released N-terminal fragment has not yet been described. Full length IL-33 localizes to the nucleus where it associates with heterochromatin and mitotic chromosomes.1, 2, 5 Both of these interactions are mediated by the HTH motif but not the NLS.5 IL-33 functions in this context as a transcriptional repressor, although particular target genes have not been identified.5
The C-terminal fragment of IL-33 is the only cytokine that has been shown to bind the receptor ST2L.3, 7, 8, 9 The IL-33/ST2L complex subsequently associates with IL-1R AcP to enable IL-33-dependent activation of NFkB.3, 10 IL-1R AcP is a shared signaling subunit that also associates with IL-1 RI and IL-1 R6. Extracellular IL-33 promotes Th2-biased immune responses, resulting in eosinophilia and allergic inflammation. In Th2 cells, it upregulates the production of IL-4, IL-5, and IL-13 as well as ST2L.3, 10 In mast cells, it cooperates with TSLP in inducing the production of several cytokines and chemokines but does not trigger mast cell degranulation or eicosanoid production.7 Alternative splicing of ST2L generates ST2, a soluble decoy receptor that is elevated in the serum of asthma and heart failure patients.6, 8 ST2 association with IL-33 blocks ST2L-dependent signaling and the immunological and cardiac effects of IL-33.6, 7, 8 The IL-33/ST2L system has a distinct role in the heart. IL-33 counteracts cardiac myocyte hypertrophy, which is induced by angiotensin II or phenylephrine.6 This cardioprotective effect is reliant on ST2L-mediated signaling.6 In parallel to the induction of IL-33 in cardiac fibroblasts, ST2 is induced in cardiac myocytes by mechanical stress.6
View Larger Image
|Full length IL-33 (Pro IL-33) localizes to the nucleus where it inhibits gene transcription. The C-terminal cytokine-like fragment of IL-33 is released and binds ST2L. Ternary complexes of IL-33/ST2/IL-1R AcP transduce signals that result in increased expression of proteins involved in allergic inflammation.|
IL-33 shows similarities to IL-1 alpha and HMG-B1 in that it exhibits both nuclear and extracellular functions.4 Unlike those factors, however, little is known about the regulation of the full length and processed forms of IL-33. Further investigations will likely uncover relationships between its transcriptional targets, chromosome binding, immune and cardiac functions, and potential signaling crosstalk induced by other cytokines that utilize IL-1R AcP.