Stem Cell Factor Programs the Mast Cell Activation Phenotype

Abstract

Mast cells, activated by antigen via the high affinity receptor for IgE (FcεRI), release an array of pro-inflammatory mediators that contribute to allergic disorders such as asthma and anaphylaxis. The KIT ligand, stem cell factor (SCF), is critical for mast cell expansion, differentiation and survival, and, under acute conditions, enhances mast cell activation. However, extended SCF exposure in vivo conversely protects against fatal antigen-mediated anaphylaxis. In investigating this dichotomy, we identified a novel mode of regulation of the mast cell activation phenotype through SCF-mediated programming. We found that mouse bone marrow-derived mast cells chronically exposed to SCF displayed a marked attenuation of FcεRI-mediated degranulation and cytokine production. The hypo-responsive phenotype was not a consequence of altered signals regulating calcium flux or protein kinase C, but of ineffective cytoskeletal reorganization, with evidence implicating a down-regulation of expression of the Src kinase Hck. Collectively, these findings demonstrate a major role for SCF in the homeostatic control of mast cell activation with potential relevance to mast cell-driven disease and the development of novel approaches for the treatment of allergic disorders.

A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection

“…A decrease in expression of IgE receptors or other molecules relevant to MC activation in KIT D186V-transformed cells was excluded in our experiments. However, Itoh et al 49 have recently shown that MCs chronically exposed to SCF display a marked attenuation of FceRImediated degranulation and cytokine production. Such desensitization may also play a role in KIT D816V-positive cells in which the KIT receptor is chronically phosphorylated.…”

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…Because masitinib inhibits various tyrosine kinases, including c-Kit, CSF-1R, PDGF-R, Lyn, and Fyn, it could potentially downregulate other cell types, including mast cells as well as monocytes and macrophages (25,26). In particular, c-Kit receptor activation by stem cell factor is needed for the differentiation of mast cells from precursors (65). It is presently unknown whether stem cell factor is upregulated in ALS-affected muscles; however, it could be expressed by Schwann cells, as described previously in neurofibromatosis type-1 (66).…”

Analyzing the Functions of Mast Cells <em>In Vivo</em> Using '<em>Mast Cell Knock-in</em>' Mice

“…may influence the phenotype and function of such cells. For example, it has been reported that BMCMCs chronically exposed to SCF have increased levels of histamine and certain proteases 44,46 , but display a marked attenuation of FcεRI-mediated degranulation and cytokine production in vitro 45 . Finally, in addition to IL-3, WEHI-3-conditioned medium contains many biologically active molecules that may affect MC functions.…”

“…However, recombinant IL-3 (10 ng/ml, as described in step 1.2.1) can also be used, and addition of recombinant stem cell factor (SCF) to the culture medium can substantially enhance the numbers of BMCMCs generated 42,43 . Depending on the study, 10 to 100 ng/ml of recombinant SCF have been used, in addition to IL-3, to generate BMCMCs 36,44,45 . One should keep in mind that commercially available murine recombinant SCF preparations from different suppliers may differ in their potency in influencing the development of BMCMCs.…”