IL33ST2L

IL33ST2L refers to the interleukin-33 receptor subunit ST2L, a protein encoded in humans by the IL1RL1 gene. It is a member of the interleukin-1 receptor/Toll-like receptor superfamily and functions as the transmembrane component of the IL-33 receptor. Binding of the cytokine IL-33 to ST2L initiates signal transduction through the MyD88 adaptor protein, activating downstream pathways such as NF-κB and MAP kinases, which drive the expression of inflammatory and type 2 immune response genes.

The IL1RL1 gene also produces soluble isoforms, most notably soluble ST2 (sST2), via alternative splicing. Unlike ST2L, sST2 lacks the transmembrane domain and acts as a decoy receptor by binding IL-33 in the extracellular space, thereby modulating or dampening IL-33–driven signaling. This balance between membrane-bound ST2L and soluble ST2 influences the magnitude of IL-33–mediated responses.

Expression of ST2L is widespread across various cell types involved in immunity and inflammation, including Th2 cells, mast cells, eosinophils, group 2 innate lymphoid cells, endothelial cells, and fibroblasts. The IL-33/ST2 axis promotes type 2 immunity and can contribute to allergic diseases such as asthma and atopic dermatitis, as well as tissue remodeling and fibrosis in certain contexts.

Clinical relevance is underscored by the utility of sST2 as a biomarker in cardiovascular disease, where elevated levels correlate with adverse outcomes. Genetic variants in IL1RL1 and differential regulation of ST2L and sST2 are areas of ongoing research in immunology and inflammatory disease.