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- Enoksson, Mattias, et al.
(författare)
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Intraperitoneal influx of neutrophils in response to IL-33 is mast cell-dependent
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:3, s. 530-536
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Tidskriftsartikel (refereegranskat)abstract
- IL-33 is a recently discovered cytokine involved in induction of Th2 responses and functions as an alarmin. Despite numerous recent studies targeting IL-33, its role in vivo is incompletely understood. Here we investigated inflammatory responses to intraperitoneal IL-33 injections in wild-type and mast cell–deficient mice. We found that wild-type mice, but not mast cell–deficient Wsh/Wsh mice, respond to IL-33 treatment with neutrophil infiltration to the peritoneum, whereas other investigated cell types remained unchanged. In Wsh/Wsh mice, the IL-33–induced innate neutrophil response could be rescued by local reconstitution with wild-type but not with T1/ST2−/− mast cells, demonstrating a mast cell–dependent mechanism. Furthermore, we found this mechanism to be partially dependent on mast cell–derived TNF, as we observed reduced neutrophil infiltration in Wsh/Wsh mice reconstituted with TNF−/− bone marrow–derived mast cells compared with those reconstituted with wild-type bone marrow–derived mast cells. In agreement with our in vivo findings, we demonstrate that humanneutrophils migrate toward the supernatant of IL-33–treated human mast cells. Taken together, our findings reveal that IL-33 activates mast cells in vivo to recruit neutrophils, a mechanism dependent on IL-33R expression on peritoneal mast cells. Mast cells activated in vivo by IL-33 probably play an important role in inflammatory reactions.
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| 4. |
- Westerberg, C Möller, et al.
(författare)
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Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
- 2012
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 3, s. e417-
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Tidskriftsartikel (refereegranskat)abstract
- The majority of patients with systemic mastocytosis exhibit a D816V mutation in the activating loop of the Kit receptor expressed on mast cells. The Kit ligand regulates mast cell survival by transcriptional repression of the proapoptotic BH3-only protein Bim and by promoting Bim phosphorylation that makes it vulnerable for proteasomal-dependent degradation. We investigated here whether prevention of Bim degradation by a proteasomal inhibitor, MG132, would induce apoptosis in mast cells with the D816V mutation. Human umbilical cord blood-derived mast cells (CBMCs) with wild-type (wt) Kit and two different subclones of the human mast cell line-1 (HMC-1) were used for the study: HMC-1.1 with the V560G mutation in the juxtamembrane domain and HMC-1.2 carrying the V560G mutation together with the D816V mutation. MG132 at 1 μM induced apoptosis in all cell types, an effect accompanied by increased BH3-only proapoptotic protein Bim. The raise of Bim was accompanied by caspase-3 activation, and a caspase-3 inhibitor reduced MG132-induced apoptosis. Further, MG132 caused a reduction of activated Erk, a negative regulator of Bim expression, and thus Bim upregulation. We conclude that decreased phosphorylation and increased levels of Bim overcome the prosurvival effect of the D816V mutation and that the results warrant further investigations of the clinical effects of proteasomal inhibition in systemic mastocytosis.
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