Regulation of Human Lung Mast Cell Responses by Stem Cell Factor

Stem Cell Factor (SCF) is widely recognised as a crucial growth factor for mast cells and has been shown to mediate the development, differentiation and proliferation of mast cells from precursors. These effects of SCF are thought to be mediated by the c-KIT receptor. Whether SCF directly activates mast cells is more contentious and most of the data suggests that SCF can ‘prime’ mast cells for enhanced responses to IgE-dependent activation. The principal aim of the present work was to determine whether SCF activates human lung mast cells. Our studies showed that SCF was an effective direct activator of human lung mast cells. Although not as effective as anti-IgE at inducing histamine release, nonetheless, in about a third of all mast cell preparations, SCF induced substantial levels of release. Even more strikingly, SCF was as effective as anti-IgE at inducing prostaglandin D2 (PGD2) generation from mast cells. By contrast, SCF was relatively ineffective at inducing cytokine generation from human lung mast cells, a feature shared by other stimuli such as anti-IgE. The effects of SCF on histamine and PGD2 release were blocked by the c-KIT inhibitors imatinib, dasatinib and nilotinib suggesting that SCF acts through the c-KIT receptor to activate mast cells. Further studies were performed to evaluate the mechanism by which SCF and anti-IgE drive PGD2 generation from mast cells. In particular, the role of the enzyme cyclooxygenase (COX) on PGD2 generation was evaluated. Studies utilising COX-1 and COX-2 selective inhibitors demonstrated that COX-1 was the isoform that drives PGD2 generation from mast cells. This finding was further supported by Western blotting studies showing that COX-1 is the principal isoform expressed by mast cells. In total, these findings indicate that SCF can directly activate human lung mast cells through the c-KIT receptor to generate substantial amounts of PGD2 and variable amounts of histamine. The data also show that COX-1 is the principal isoform involved in PGD2 generation from human lung mast cells. Overall these studies indicate that SCF is a far more effective activator of human lung mast cells than hitherto appreciated.