Signal Transduction in Mast Cell Migration

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Mast cells are essential effector cells in the immune system as they release several inflammatory mediators. An accumulation of mast cells has been described in inflammatory conditions such as asthma and allergic rhinitis. Increased mast cell number, in the skin and other organs, is also a characteristic in mastocytosis, a disease without an effective treatment. One explanation for the increase in mast cell number is migration of mast cells in the tissue. In our studies we utilised mast cell lines, including HMC-1; cell lines transfected with the c-kit gene; and in vitro developed mast cells.Our aim was to characterise, two variants of the HMC-1 cell line; the signalling pathways essential for mast cell migration towards TGF-β and SCF; and the mechanism regulating mast cell accumulation in mastocytosis.Our results help to explain inconsistent findings regarding mast cell biology when HMC-1 cells have been used as a model system. The two variants, which we name HMC-1560 and HMC-1560, 816, are used in different laboratories around the world. HMC-1560 and HMC-1560, 816 exhibited different characteristics regarding their karyotype, phenotype as well as their set of activating point mutations in the Kit receptor. Furthermore, divergent signalling pathways are of importance for mast cell migration towards TGF-β and SCF. The classical MAP kinase-signalling cascade was found to be of major relevance for TGF-β-induced migration. In contrast, this pathway had a modest impact on SCF-induced migration, which instead was highly dependent on p38 MAP kinase signalling. Finally, one mechanism for mast cell accumulation in mastocytosis appeared to be an activating point mutation in the gene for the Kit receptor. This mutation appeared to prone transfected cells and mast cell progenitors to a higher rate of migration towards SCF if compared with cells expressing wt Kit receptor.In conclusion, our results show the importance of two different MAP kinase signalling pathways and mutations in the Kit receptor for mast cell migration induced by various types of stimuli. This knowledge helps us to understand the mechanism

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