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…
Contents
INTRODUCTION
MAST CELLS
Introduction
Mast cells are hematopoietic cells
Distribution, morphology and heterogeneity of mast cells
Mice with W and Sl mutations lack mast cells
The characterisation of Kit and SCF
The role of Kit and SCF in hematopoiesis
The role of Kit and SCF in mast cell biology
Mast cells contain and release inflammatory mediators
Mast cell responses to bacteria and parasites
Mast cells in wound healing and carcinogenesis
The role of mast cells in angiogenesis
MAST CELL HYPERPLASIA
Regulation of mast cell hyperplasia
THE ROLE OF SCF OUTSIDE THE HEMATOPOIETIC SYSTEM
Melanocytes
Germ cells and CNS
INTRACELLULAR SIGNALLING INDUCED BY SCF
Receptor-dimerisation
PI3-kinase
JAK/STAT
MAP kinase
p38 MAP kinase
Src family
Phosphatases
INTRACELLULAR SIGNALLING INDUCED BY TGF-β
Smads
Other signalling pathways induced by TGF-β
MOLECULAR MECHANISM MEDIATING CELLULAR MIGRATION
KIT IN DISEASE
c-kit mutations
Mastocytosis
Gastrointestinal stromal tumours
AIMS OF THE PRESENT INVESTIGATION
RESULTS AND DISCUSSION
Paper I
Paper II
Paper III
Paper IV
ACKNOWLEDGEMENT
REFERENCES
Author: Sundstrom, Magnus
Source: Uppsala University Library
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