The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells

Abstract

Members of the Toll/interleukin-1 receptor (TIR) family are of importance for host defense and inflammation. Here we report that the TIR-family member interleukin-33R (IL-33R) cross-activates the receptor tyrosine kinase c-Kit in human and mu-rine mast cells. The IL-33R-induced activation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), protein kinase B (PKB), and Jun NH 2-terminal kinase 1 (JNK1) depends on c-Kit and is required to elicit optimal effector functions. Costimulation with the c-Kit ligand stem cell factor (SCF) is necessary for IL-33-induced cytokine production in primary mast cells. The structural basis for this cross-activation is the complex formation between c-Kit, IL-33R, and IL-1R accessory protein (IL-1RAcP). We found that c-Kit and IL-1RAcP interact constitu-tively and that IL-33R joins this complex upon ligand binding. Our findings support a model in which signals from seemingly disparate receptors are integrated for full cellular responses. (Blood. 2010; 115(19):3899-3906)

A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

“…Mutation of Y823 leads to increased c-Kit internalisation and degradation, suggesting a role for this site . Activation of these pathways is implicated in numerous cellular processes, such as gene transcription, cellular proliferation, differentiation, survival and adhesion [16][17][18][19][20][21][22][23][24][25][26][27]. Src homology region 2 domain-containing phosphatase-1 (SHP-1), Casitas b-lineage lymphoma (c-Cbl), SOCS and the protein kinase C signals (brown) are involved c-Kit downregulation.…”

“…c-Kit signalling pathways are not simple linear reactions, but, rather, integrated inputs from different pathways that determine the biological consequences in different cellular contexts. For instance, c-Kit crosstalks with the erythropoietin receptor or interleukin receptors to recruit common downstream signalling molecules, creating a method for modulating diverse physiological responses [26][27][28][29].…”

“…It has been documented that c-Kit is able to crosstalk with many growth factor and cytokine receptors [26][27][28]81]. For example, erythropoietin and SCF have synergistic effects on erythropoiesis.…”

Endogenous IL-33 Is Highly Expressed in Mouse Epithelial Barrier Tissues, Lymphoid Organs, Brain, Embryos, and Inflamed Tissues: In Situ Analysis Using a Novel Il-33–LacZ Gene Trap Reporter Strain

“…I nterleukin-33 (previously known as NF from high endothelial venules) (1, 2) is an IL-1-like cytokine that signals through the ST2 receptor (3) and drives production of cytokines and chemokines in target cells (4,5), including mast cells (6)(7)(8), basophils and eosinophils (9), endothelial cells (10), Th2 lymphocytes (3), and invariant NKT and NK cells (11,12). IL-33 is also a potent activator of type 2 innate immune cell populations that have been described recently, including natural helper cells from adipose tissues and lung (13,14), nuocytes from mesenteric lymph nodes and spleen (15), and innate helper 2 cells from various tissues (16).…”

Perinatal Immune Activation and Risk of Autism

“…It is intriguing that mast cell-derived IL-9 induces intestinal permeability and predisposes to oral antigen hypersensitivity in children (Forbes et al, 2008), while it also exacerbates newborn brain toxic lesions (Dommergues et al, 2000). Moreover, IL-33 can synergize with SP and SCF (Drube et al, 2010) in stimulating mast cell TNF release, while it also activates glial cells to secrete proinflammatory cytokines (Yasuoka et al, 2011). The possible involvement of mast cells in ASD is also supported by the fact that many children with ASD report "allergic-like" symptoms .…”