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 κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB 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.

IL‐33‐activated murine mast cells control the dichotomy between RORγt+ and Helios+Tregs via the MK2/3‐mediated IL‐6 production in vitro

“…However, instead of MK2/3, ERK1/2 and Lyn are essential for the phosphorylation of S727 and surprisingly also of Y705 of STAT3 upon SCF stimulation. Different from the IL‐33‐induced signaling, the role of MK2/3 is limited to the control of the proliferation induced by high SCF concentrations . This is in accordance to our finding that the frequencies of CTMCs in wt and mk2/3 −/− mice were similar under homeostatically low SCF concentrations in vivo .…”

“…A and B). Together with our earlier findings , these data indicate that MK2/3 limits the proliferation but not the differentiation of mast cells by controlling the IKK2‐JNK1/2 signaling module.…”

“…D) in mast cells. Whereas inhibition of ERK, also only partly ( and Fig. E), reduced the IL‐33‐induced IL‐6 response, the IL‐2 production was strongly reduced (Fig.…”

“…The SCF‐induced proliferation depends on IKKs and JNKs in mast cells . Whereas the SCF‐induced activation of c‐Kit, STAT5, and ERK1/2 was similar in wt and mk2/3 −/− BMMCs (Fig.…”

“…E). Compared to IL‐3, SCF is a weaker inducer of mast cell proliferation . To investigate the role of MK2/3 in the SCF‐induced proliferation, we investigated the proliferation rate in wt and mk2/3 −/− BMMC stimulated with different SCF concentrations.…”