Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, mediates its effects through a heterodimer consisting of ST2L and an as-yet-unidentified second receptor. IL-33 stimulates the production of cytokines associated with a T helper 2 (Th2) response, including IL-5 and IL-13. ST2L is homologous to the ligand-binding subunits of the receptors for the IL-1 family members IL-1 and IL-18. Some members of the IL-1 family use the second component of the IL-1 receptor (IL-1R) complex, the IL-1R accessory protein (IL-1RAcP), so Chackerian et al. investigated whether IL-1RAcP was the second component of the IL-33R complex. The administration of recombinant IL-33 to wild-type mice resulted, as expected, in a systemic inflammatory response, as measured by immunohistochemical analysis of the small intestine and quantification of serum levels of IL-5 (and other cytokines) by enzyme-linked immunosorbent assay (ELISA). However, none of these effects were observed in IL-33-treated mice that were deficient in IL-1RAcP (IL-1RAcP KO mice). Real-time reverse transcription polymerase chain reaction (RT-PCR) assays demonstrated the increased abundance of mRNAs for proinflammatory cytokines in the lungs of IL-33-treated wild-type mice compared with those of IL-1RAcP KO mice. Whereas CD4+ T cells from wild-type and IL-1RAcP KO mice could be activated under Th2-polarizing conditions in vitro, only wild-type cells responded to IL-33 treatment to enhance secretion of IL-5 and IL-13. The authors used ELISA to detect the binding of soluble IL-33 and epitope-tagged IL-1RAcP to plate-bound ST2. IL-33R signaling results in the activation of the transcription factor nuclear factor κB (NF-κB). This activation depends on the adaptor protein MyD88, which contains a Toll-IL-1R (TIR) domain, as does IL-1RAcP. IL-33 treatment of a cell line expressing ST2L and a truncated IL-1RAcP (missing the TIR domain) resulted in less activation of NF-κB than did IL-33 treatment of cells expressing ST2L with wild-type IL-1RAcP, as assessed by fluorescence-based reporter assays. In a related study, Allakhverdi et al. examined the effects of IL-33 on mast cells, which express ST2. Treatment of human mast cells with IL-33 resulted in the secretion of proinflammatory chemokines and cytokines. Mast cells are derived from CD34+ progenitor cells, which can be activated by thymic stromal lymphopoietin (TSLP). The authors found that IL-33, either alone or in combination with TSLP, induced the maturation of CD34+ cells into mast cells. Mast cells are important in allergic responses, which are often characterized by the presence of Th2-associated cytokines, so the action of IL-33, a Th2-promoting cytokine, on mast cells may have clinical relevance. Together, these studies provide new insights into the role and mechanism of IL-33 signaling and may have implications for other members of the IL-1 family that use IL-1RAcP and for understanding the contributions of mast cells to Th2 immune responses.
A. A. Chackerian, E. R. Oldham, E. E. Murphy, J. Schmitz, S. Pflanz, R. A. Kastelein, IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J. Immunol. 179, 2551-2555 (2007). [PubMed]
Z. Allakhverdi, D. E. Smith, M. R. Comeau, G. Delespesse, Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J. Immunol. 179, 2051-2054 (2007). [PubMed]