Regulation of Prostaglandin, Leukotriene, and Platelet-Activating Factor Metabolism in Mast Cells

Abstract

There are at least two distinct populations of mast cells: connective tissue mast cells (CTMC) and mucosal mast cells (MMC). CTMC contain heparin proteoglycan, CTMC-specific proteases and large amounts of histamine, and respond to Fc_eRI-dependent activation with preferred generation of the cyclooxygenase (COX) pathway product, prostaglandin (PG) D₂. MMC contain chondroitin sulfate proteoglycan, MMC-specific proteases, and less histamine than CTMC, and generate leukotrime (LT) C4 via the 5-lipoxygenase (5-LO) pathway in preference to PGD2 following Fc_eRI-dependent activation. Mouse bone marrow-derived mast cells (BMMC) developed in interleukin (IL)-3, a progenitor population of mast cells, resemble MMC in terms of their granule contents and preferred Fc_eRI-dependent LTC4 generation, but express mast cell proteases different from those expressed in CTMC and MMC. Coculture of BMMC with 3T3 fibroblasts results in morphological and functional development toward a more mature CTMC-like phenotype. Many of these alterations are supported by the stromal cytokine, c-kit ligand (KL). Another fibroblast-derived cytokine, nerve growth factor (NGF), and several hematopoietic cytokines, such as IL-3, IL-4, IL-9 and IL-10, either alone or in combination, modulate the proliferation and maturation of mast cells in vitro. Recent advances in molecular biology as well as culture techniques have enabled us to identify the regulatory mechanisms of the lipid mediator metabolism in mast cells. In this paper, we describe the regulation of the biphasic PGD₂ biosynthetic pathways in activated mast cells, developmentally segregated regulation of the PGD₂ and LTC4 pathways in lineage-related committed mast cell progenitors, and an intriguing anti-inflammatory action of mast cells, degradation of platelet-activating factor (PAF).