Mast cell histamine synthesis

Synthesis Histamine is an amine formed by the decarboxylation of the amino acid histidine (Figure 40.3). This process occurs primarily in the mast cells, basophils, and in the lungs, skin, and gastrointestinal mucosa—the same tissues in which histamine is stored. In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the polysulfated anion, heparin, along with an anionic protein. If histamine is not stored, it is rapidly inactivated by amine oxidase enzymes. 

Synthesis. Histamine [51-45-6] 2-(4-imidazolyl)ethylarnine (1) is formed by decarboxylation of histidine by the enzyme L-histidine decarboxylase (Fig. 1). Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases the skin, respiratory tract, and gastrointestinal tract. 

Although mast cells and basophils probably account for >90% of stored histamine in the body, histamine is also present in platelets, enterochromaffin-like cells, endothelial cells, and neurons. Histamine can act as a neurotransmitter in the brain. Histaminergic nerves have their cell bodies within a very small area of the brain (the magnocellular nuclei of the posterior hypothalamus) but have axons in most areas of the forebrain. There is also evidence for axons projecting into the spinal (Fig. 1) cord. Finally, there is evidence that histamine synthesis can be induced in tissues undergoing rapid tissue growth and repair. In certain neonatal tissues (e.g. liver), the rate of synthesis of this unstored diffusable histamine (termed nascent histamine) is profound and may point to a role for histamine is cell proliferation. 

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. 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

Figure 4.8. Hypothesis for the local generation of mast-cell-stimulating peptides by the action of neutrophil-derived enzymes on albumin. Initial stimulation of the mast cell by any of a variety of agents causes the release of preformed histamine (H) neutrophil and eosinophil chemotactic factors (NCF, ECF) and enzymes and the de novo synthesis of prostaglandins (PG) and leukotrienes (LT). These agents increase vascular permeability and vessel diameter. As a result, albumin and later neutrophils (PMN) enter the tissue space where the latter undergo phagocytosis and the secretion of proteolytic enzymes to the extracellular space where they act on albumin to generate NRP (neurotensin-related peptide) and HRP (histamine-releasing peptide). These newly formed peptides then act as a second stimulus to the mast cell. In addition NRP and HRP may affect other immunocompetent celt such as monocytes, macrophages or eosinophils.

The classical cellular sources of histamine are mast cells and basophils, gastric enterochromaffin-like cells, platelets and histaminergic neurons. Interestingly the cells in the immune system, which do not store histamine, show high HDC activity and are capable of production of high amounts of histamine, which is secreted immediately after synthesis [20]. These cells include platelets, monocytes/macrophages, DCs, neutrophils, and T and B lymphocytes. 

Tanaka S. Takasu Y, Mikura S, Satoh N, Ichikawa A Antigen-independent induction of histamine synthesis by immunoglobulin E in mouse bone marrow-derived mast cells. J Exp Med 2002 196 229-235. 

Histamine is synthesized from the amino acid histidine by an action of the enzyme histidine decarboxylase (Fig. 38.1). Following synthesis, histamine is either rapidly inactivated or stored in the secretory granules of mast cells and basophils as an inactive complex with proteases and heparin sulfate or chondroitin sulfate. 

Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release. Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells. 

Synthesis. Histamine, 2-(4-imidazolyl)ethylamine, is formed by decarboxylation of histidine by the enzyme l.-histidinc decarhoxylase. Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. 

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. 

H3 receptor activation in the airway system of the guinea pig caused a decrease in histamine release from mast cell and/or basophils and the H3 antagonist had the opposite effect. As far as histamine synthesis is concerned, the allergen-exposure induced histamine forming capacity could be increased by thioperamide, even though (R)a-methylhistamine was completely inactive. The explanation given for this peculiar phenomenon was that the histamine... 

Bradykinin and related kinin peptides are produced by leucocytes and act via Gaq to elevate cytosolic Ca2+ and promote nitric oxide (NO) synthesis, smooth muscle contraction, capillary permeability, inflammation and histamine release from mast cells. 

Glucocorticoids also have antiallergic properties, as a result of and by an inhibition of the synthesis of histamine by mast cells and basophils. Of the naturally occurring corticosteroids, only cortisol and corticosterone possess glucocorticoid activity, with cortisol the most effective. Cortisone and 11-dehydrocorticosterone lack direct glucocorticoid activity, but have potential glucocorticoid activity because they can be metabolixed to cortisol and corticosterone, respectively. 

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... 

HCV has been associated with many extrahepatic manifestations [35, 36, 67], including myocarditis and cardiomyopathy [68, 69]. Histological and functional observations have led to the hypothesis that mast cells play an important role in many fibrotic reactions [70-72], Potential mast cell-derived mediators of the fibrotic response include histamine, tryptase and TGF-fl, which stimulate fibroblast proliferation and collagen synthesis [73-75]. By producing these factors, chronic activation of cardiac mast cells by protein Fv may contribute to the heart fibrosis found in some patients with HCV infection [68, 69]. 

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