Role For Itk Research Articles

Itk acts as a negative regulator in mast cell activation (91.19)

Abstract Mast cells are key effectors of allergic and innate immune responses and have been implicated as 'immuno-modulators' in adaptive immunity. Mast cell activation through the immuno-receptor, FceR1, propagates a complex signaling cascade which culminates in a broad range of effector functions. Central to this signal transduction are various protein tyrosine kinase families including members of the Tec family. The Tec family kinases, Itk and Btk, have been extensively studied in T cells and B cells, respectively, and have been shown to play positive signaling roles. Deficiency in either of these two kinases results in diminished signal transduction downstream of their respective immuno-receptors leading to defects in development as well as effector function. In contrast to T cells and B cells, mast cells express both Itk and Btk at similar levels. Btk-deficient mast cells exhibit a decreased effector function consisting of reduced degranulation and cytokine production. Furthermore, this phenotype is accompanied by diminished signal transduction downstream of FceR1, as shown by decreased Ca2+ flux and PLCγ phosphorylation. Here we show that Itk-deficient mast cells display almost the opposite phenotype. These mast cells show enhanced levels of Th2-associated cytokines as well as some pro-inflammatory factors. We show that signal transduction events downstream of FceR1, including Ca2+ flux and PLCγ phosphorylation, are enhanced in the absence of Itk. Additionally, we show that Itk interacts with and phosphorylates the phosphatase, SHIP-1, a negative regulator in mast cells. Finally, we show that Itk co-localizes with a negative signaling complex in wild-type mast cells. Taken together, these data indicate that Itk can impact mast cell activation by dampening the Ag-mediated response. This work suggests a novel role for Itk as a negative regulator in mast cell signaling.