白介素33信号通路图

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IL-33 may be released by damaged epithelial Cell s in response to various noxious agents, and induce the release of several proinflammatory cytokines by cells expressing ST2, such as mast cells, eosinophils and M2-polarized macrophages, leading to the recruitment of additional eosinophils. Downstream activation of fibroblasts by IL-13 and other cytokines will lead to the production of collagen and eventually to tissue fibrosis.

The activation of other ST2-expressing cells, including basophils and dendritic cells, might contribute to the polarization of TH2 cells. IL-33 exerts dual functions on TH2 cells: it acts not only as an activator and chemoattractant, but also as a regulator, by reducing production of IL-5. Endothelial cells and activated fibroblasts produce IL-33, thus further amplifying local inflammatory responses. Abbreviations: CCL, CC-chemokine ligand; IL, interleukin; TGF, transforming growth factor; TH2 cell, type 2 T helper cell; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor.

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IL-33 signaling occurs via the ST2L receptor. Binding of IL-33 to ST2L induces the recruitment of IL-1RAcP and activation of intraCell ular signaling pathways including MyD88 and TRAF6-dependent activation of NFκB, p38 and JNK, as well as Myd88-dependent activation of ERK. JAK2 has also been shown to be involved in NFκB activation.

Crosstalk of IL-33 with c-kit signaling has been proposed to enhance the activation of ERK, JNK, PKB and STAT3 in mast cells. In monocytes, IL-33 was reported to activate Syk, GAB2, and PLC-γ2, suggesting potential crosstalk with ITAM-bearing receptors. b | Negative regulators of the IL-33–ST2L pathway include sST2 and sIL-1RAcP, which act as decoy receptors for IL-33, as well as SIGIRR, which interferes with intracellular ST2L signaling.

Abbreviations: GAB2, GRB2-associated-binding protein 2; IL, interleukin; IL-1RAcP, IL-1 receptor accessory protein; IRAK, IL-1 receptor-associated kinase; ITAM, immunoreceptor tyrosine-based activation motif; JAK, Janus kinase; NFκB, nuclear factor κB; PKB, protein kinase B; PLC,

phospholipase C; SIGIRR, single Ig IL-1-related receptor; sIL-1RAcP, soluble IL-1 receptor accessory protein; sST2, soluble ST2; STAT3, signal transducer and activator of transcription 3; TRAF6, tumor necrosis factor receptor-associated factor 6.