IL-33: A Sheep in Wolf’s Clothing?

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Abstract
Cytokines are soluble factors that regulate intercellular communication by binding to specific cell-surface receptors and activating cellular responses. A small subset of cytokines, however, has been recognized to act in an intracrine manner without being secreted. These molecules enter the nucleus and regulate gene transcription by binding nuclear coactivators or repressors. Interleukin-33 (IL-33), a cytokine with high sequence and structural similarity to IL-1 and IL-18, has now been identified as another member of this group of "double agents." The activity of IL-33, however, appears to be the opposite of other dual-activity molecules such as the proinflammatory molecules, IL-1 and HMBG1 (high-mobility group box 1). Soluble IL-33 binds the Toll-interleukin 1 (IL-1) receptor (TIR) domain-containing receptor ST2 and has T helper 2 (Th2) immunoregulatory activity. ST2 also inhibits the activity of Toll-like receptors (TLRs) by sequestering the TLR adaptor molecules MyD88 and Mal. The HMBG1 receptor pairs with TLRs and helps drive responses to infections, raising the possibility that ST2, acting as a coreceptor for TLRs, could modulate and perhaps limit immune responses to pathogens. The nuclear targets of IL-33 are still unknown, but the expression of IL-33 in inflamed tissues, its nuclear repressor activity, and the antagonistic properties of ST2 suggest that it could decrease inflammation, opposing the activity of factors like IL-1. If this holds true, IL-33 has potential as a novel therapeutic in autoimmune and inflammatory diseases.