Regulation of mast cell number and function

Since the original identification by Ehrlich in 1877(23) of mast cells in human connective tissues, the understanding of the origin, regulation of mast cell growth, differentiation, survival, and apoptosis, mediator release and function and more recently, signal transduction events has increased considerably. Indeed, studies of rodent and human mast cells show that mast cells are complex, well-engineered, multifunctional cells that are central to innate and acquired immunity rather than involved solely in host responses against parasitic infections or allergic inflammation.(80, 84) Furthermore, one can no longer draw conclusions concerning human mast cells from studies involving rodent mast cells, because there are phenotypic differences or differences in regulation of mast cell number and function. Rodent mast cells, for example, have been classified as connective tissue (atypical) and mucosal (typical) based on metachromatic staining with acidic toluidine blue and alcian blue, on granule proteoglycan and protease content, and location within tissues.(16) Immunocytochemical studies of human tissues initially showed the presence of two mast cell (MC) phenotypes distinguishable by their neutral protease content: the MC, phenotype containing only tryptase, and the MCTC phenotype containing both tryptase and chymase. Initially these subtypes were thought to be the equivalents of the rodent mucosal and connective-tissue mast cells, respectively. It is now realized that variable amounts of both mast cell subtypes are present within any given tissue and that their relative abundance changes with disease states such as allergy or fibrosis.(16) A third mast cell phenotype, the MCC cell that rodent mast cell cultures expand in the presence of interleukin (IL)-3(44) and IL-4.(9) In contrast, primary long-term human mast cell cultures require stem cell factor (SCF) which is synergistic with IL-3(22) but is inhibited by IL-4.(127) The classification, therefore, of human mast cells, based on phenotype and regulation of growth characteristics, is unique and does not conform to the rodent model. These important differences must be cortsidered when engaging in human mast cell research. Two additional developments are significant for the understanding of the regulation of mast cell numbers and function. First, the characterization and cloning of SCE the ligand to the receptor encoded by the proto-oncogene c-kit and produced primarily by stromal cells, endothelial cells, fibroblasts, and keratinocytes, has enabled large numbers of human mast cells to be cultured from CD34+ progenitors for studies of various aspects of mast cell biology (Arnold Kirshenbaum, MD, unpublished observations, October 1999). Second, mast cell numbers may be controlled by agents that increase the cell divisions and also by factors that prevent apoptosis. Indeed, no report describes any growth factor in mast cells that does not have an antiapoptotic capability.(8) Therefore, much of the effect of the mast cell growth factors might be caused by the suppression of mast cell apoptosis as well as by a proliferative and differentiation capacity. The action of growth factors will differ, depending on culture conditions and on whether primary cultures or mast cell lines are studied. It is therefore important to describe the biologic system in which the effects of growth factors on mast cell numbers and function were evaluated. This review presents recent advances in the understanding of cytokine regulation of mast cell numbers and function in rodents and humans and in some of the cellular growth control networks which may occur in vivo at sites of mast cell growth.