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Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells.

ABSTRACT: Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca²?-dependent activation of the inhibitor of ?B kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce I?B?-degradation and NF?B activation. Therefore we propose the term "subthreshold IKK activation".This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33.We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo.Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.

SUBMITTER: Drube S

PROVIDER: S-EPMC4467154 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells.

Drube Sebastian S Weber Franziska F Loschinski Romy R Beyer Mandy M Rothe Mandy M Rabenhorst Anja A Göpfert Christiane C Meininger Isabel I Diamanti Michaela A MA Stegner David D Häfner Norman N Böttcher Martin M Reinecke Kirstin K Herdegen Thomas T Greten Florian R FR Nieswandt Bernhard B Hartmann Karin K Krämer Oliver H OH Kamradt Thomas T

Oncotarget 20150301 7

Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca²⁺-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose ...[more]

PMID: 25749030

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Project description:Mast cells have essential effector and immunoregulatory functions in IgE-associated allergic disorders and certain innate and adaptive immune responses, but the role of miRNAs in regulating mast cell functions is almost completely unexplored. To examine the role of the activation-induced miRNA miR-221 in mouse mast cells, we developed robust lentiviral systems for miRNA overexpression and depletion. While miR-221 favored mast cell adhesion and migration towards SCF or antigen in trans-well migration assays, as well as cytokine production and degranulation in response to IgE-antigen complexes, neither miR-221 overexpression, nor its ablation, interfered with mast cell differentiation. Transcriptional profiling of miR-221-overexpressing mast cells revealed modulation of many transcripts, including several associated with the cytoskeleton; indeed, miR-221 overexpression was associated with reproducible increases in cortical actin in mast cells, and with altered cellular shape and cell cycle in murine fibroblasts. Our bioinformatics analysis showed that this effect was likely mediated by the composite effect of miR-221 on many primary and secondary targets in resting cells. Indeed, miR-221-induced cellular alterations could not be recapitulated by knockdown of one of the major targets of miR-221. We propose a model in which miR-221 has two different roles in mast cells: in resting cells, basal levels of miR-221 contribute to the regulation of the cell cycle and cytoskeleton, a general mechanism probably common to other miR-221-expressing cell types, such as fibroblasts. Vice versa, upon induction in response to mast cell stimulation, miR-221 effects are mast cell-specific and activation-dependent, contributing to the regulation of degranulation, cytokine production and cell adherence. Our studies provide new insights into the roles of miR-221 in mast cell biology, and identify novel mechanisms that may contribute to mast cell-related pathological conditions, such as asthma, allergy and mastocytosis.

Dataset Information

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells.

Publications

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells.

Similar Datasets

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