MOLECULAR BIOLOGY OF MAST CELL GROWTH AND DIFFERENTIATION

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The regulation of mast cell growth and differentiation depends upon the sequential availability of specific growth factors and the expression of their corresponding receptors. Among the various cytokines that promote mast cell growth, the most important is stem cell factor (SCF) which is produced in tissues by stromal cells. We have reported that the decrease in mast cells observed in tissues that follows topical steroid administration is due to the effect of the steroid on SCF production. We then explored whether mast cells undergo apoptosis in response to activation through Fas antigen (CD95, APO-1), thus providing a factor-independent pathway that could contribute to the regulation of mast cell number. The murine cell line, C57, was found to rapidly undergo apoptosis following aggregation of Fas antigen. Primary murine bone marrow derived mast cells were relatively resistant to anti-Fas antibody. Mast cells express cytoplasmic FasL only, and are unable to kill targets that express FasL. In an effect to identify cytokines that inhibit human mast cell growth, we cultured recombinant human stem cell factor (rhSCF)-dependent human bone marrow-derived mast cells (HBMCs) in the presence of interferon gamma (IFN-gamma)-1b. In these cultures HBMCs significantly decreased in number. FACS analysis of rhSCF plus IFN-gamma-1b-treated mature HBMCs revealed increased c-kit and FcERI expression. Mast cell releasibility was not increased. IFN-gamma-1b was thus able to suppress mast cell growth from CD34+ cells, suggesting that this agent should be considered as a candidate cytokine for the treatment of disorders of mast cell proliferation. The effector function of mast cells in both IgE-dependent and in immune complex-induced inflammation is in part determined by the interaction of mast cells with connective tissue matrix components including laminin. This influences mast cell chemotaxis, tissue location, and biologic responsiveness. In collaboration, we have found that SAA (serum amyloid A) bound to connective tissue matrix induces adhesion of mast cells to both this matrix and to laminin, helping to regulate mast cell recruitment at extravascular inflammatory sites.