Mast cell cytokine synthesis

The studies of mast cell cytokine production described above have shown that maximal induction of cytokine synthesis and release usually occurs in response to IgE-dependent activation. In common with many cell types, there is evidence that FccRI on mast cells is coupled to the phospholipase C effector system that controls two distinct signal transduction pathways, one regulated by Ca " ions and the other by protein kinase C (PKC). Exocytotic degranulation is associated with an increased cytoplasmic level of Ca ions, and activation of mast cells can be therefore achieved by the use of calcium iono-phores which raise intracellular calcium concentrations through a receptor-independent mechanism. Alternative mast cell stimuli include phorbol-12-myristate-13-acetate (PMA) which activates PKC and induces mediator secretion from basophils and rodent mast cells but not from human mast cells, and concanavalin A (Con A), a lectin which can stimulate mast cells by cross-linking of cell-bound IgE and/or cell surface glycoproteins. 

Type I allergic reactions are inappropriate immune responses to an allergen with preferential synthesis of immunoglobulin E (IgE), a special antibody class, which binds to mast cells and basophilic granulocytes via Fee receptors. Binding of the allergen to the cell-bound IgE initiates the rapid release of allergic mediators, most prominently histamine, and the de novo synthesis of arachidonic acid metabolites and cytokines, which are responsible for the clinical symptoms. 

The third histamine receptor subtype was found to occur on mast cells and to be involved in the synthesis and release of histamine, of nitric oxide and of a series of cytokines, even if the precise immunomodulatory function of H3 receptors is still under investigation. The bulk of data concerning H3 receptors and immunological reactions in different species and different experimental models are summarized in Table 10. 

IL-2 is the specific pattern of lymphocytes T helper 1 that increases the proliferation of T cells and activates B cells. IL-10 is a specific pattern of lymphocytes T helper 2, which is stimulatory towards certain T cells, mast cells and B cells and inhibits the synthesis of other cytokines produced by Thl. IL-10 was synthesized by cells with higher metabolic rates with respect to IL-2, suggesting a prevalent differentiation in lymphocyte immunophenotype Th2. 

IL-10 Th cells (B cells) Thi cells inhibits lymphokine synthesis Th2 cells promotes generation Monocytes inhibits cytokine synthesis Tc cells stimulates IL-2-dependent growth Mast cells stimulates growth... 

Figure 22-7 summarizes the Th2 polarization, which usually occurs because of antigenic stimulation by allergens or extraceEular antigens like hehninthic (parasite) antigens. This stimulation is associated with a lack of IL-12 and IFNy production by APCs and the absence of NK activation. However, it is dependent on mast cells and basophils, which are involved in IL-4 synthesis. Thus there is an environment rich in IL-4 (increased by the spontaneous endogenous production of this cytokine) and poor in IFNy. 

IL-10 causes the inhibition of general proinflammatory cytokine synthesis, APC function, and cell-mediated immunity and induces the terminal differentiation of B cells into plasmacytes, which results in production of antibodies. Consequently, it has important effects on T and B lymphocytes, NK cells, monocytes and/or macrophages, and mast cells. It is characterized by a paradoxical duality of function (negative and/or positive Box 22-5). 

The a-subunit of the heterotrimeric G protein, Gz, can regulate production of TNFa, modulating the stimulatory pathways for induction of this cytokine synthesis in mast cells. ... 

Episodes of airway obstruction or bronchoconstriction may be induced in asthmatics by exposure to stimuli to which they are sensitized, such as inhalation of a specific pollen or house dust mite, or exposure to an occupational stimulus, e.g., red cedar dust [47]. Binding of antigen (e.g., pollen) to specific receptors (antibodies) on the surface of an inflammatory cell (e.g., mast cell) results in the elaboration of prestored mediators, such as histamine, and in the synthesis of newly formed mediators, such as arachidonic acid metabolites (e.g., prostaglandins and leukotrienes). Cellular sources of the various mediators are shown in Table 3. Cytokines and chemokines are proteins that participate in pulmonary immune and inflammatory responses. While important, these have not been subjected to discussion in this chapter because these fields are changing very... 

IL-10 endothelial cells, fibroblasts T- and B-lymphocytes, macrophages Cytokine synthesis inhibitory factor, growth of mast cells... 

We previously showed that protein L induces proinflammatory mediator release from human basophils and mast cells, probably by interacting with FceRI-bound IgE [72, 79], We next evaluated whether protein L and a fragment of protein L denoted B1-B4 , which comprises four of the five immunoglobulinbinding repeats [73], induce cytokine (IL-4 and IL-13) synthesis and secretion from human basophils. Protein L and B,-B4 stimulated IL-4 release from basophils [80] and there was a significant correlation between IL-4 release induced by protein L and by B,-B4. These data demonstrate that protein L induces the secretion of IL-4 and IL-13, which are important for the polarization of Th2 cells [81], from basophils. 

---