Peptides histamine release

The surrounding redness caused by the vasodilatation of local blood vessels in the skin (hyperaemia). Histamine released at the site of contact acts on sensory nerve endings in the skin. Impluses travel along the axon to other peripheral branches of the same neuron to cause release of vasodilataory peptide neurotransmitters from nerve endings serving a wider area of skin than the initial contact point. Impluses reaching the CNS are interpreted as itch and pain. 

Attaching some short peptidic sequences to adamantane makes it possible to design novel antagonists. The bradykinin antagonist, which is used as an anticancer agent, is an example. The adamantane-based peptidic bradykinin analog was utilized in strucmre-activity relationship (SAR) studies on the bradykinin receptors and showed a potent activity in inhibition of bradykinin-induced cytokine release and stimulation of histamine release [142]. 

The ability of SP to stimulate histamine release from isolated rat peritoneal mast cells is now well demonstrated [31, 97-101], The release is rapid (< 1 min), non-cytotoxic, dependent on a supply of Ca and metabolic energy, and independent of cell-bound IgE [99]. Moreover, as with other peptides, its secretory effect on the mast cell is affected by moderate levels of extracellular cations. For example, the addition of Ca to the bathing medium after the addition of SP increased the secretory response of the cells, while adding calcium (0.1-1 mM), magnesium (1-10 mM) or cobalt (0.01-1 mM) to the cell suspension before SP inhibited histamine release, suggesting the possibility of cation competition for SP binding [99]. 

Like other peptides, the ability of SP to stimulate histamine release is closely related to its ability to mobilize Ca from a cellular pool and to the basic and the hydrophobic properties of its N-terminal and C-terminal amino acids, respectively. In this regard, intact SP (SP, n) is more active than the N-terminal tetrapeptide (SP8 n) with SP,, giving a half-maximal response at 8 x 10 6M and 1 x 10 5 M producing some 40% release [99], The C-terminal heptapeptide, SP, 6 was inactive [99],... 

SP seems to be the only peptide capable of stimulating histamine release from mucosal mast cells [52] and generally exhibits a pronounced heterogeneity among various tissues and between species [106],... 

Acid acetone extracts of human and rodent leukocytes (RBL-cells) have been found to contain immunoreactive SOM (iSOM) and immunoreactive SP (iSP) as determined by radioimmunoassay [144], Quantities of the peptides varied from 325 pg iSOM/107 cells for human monocytes and 272 pg iSOM/107 cells for RBL-cells to 4.4 pg iSOM/107 cells for human T cells. iSP was highest in murine bone marrow-derived mast cells (64 pg iSP/107 cells) and RBL-cells (23 pg iSP/107 cells) and lowest in human T and B lymphocytes (2.5 and 1.2 pg iSP/107 cells, respectively). Interestingly, the murine bone marrow-derived mast cells had the highest ratio of iSP to iSOM. Preliminary chromatographic results show a large and a small SOM (SOM-28 and SOM-14, respectively). SOM-14 (3 x 10 9 M) has been shown to inhibit histamine release and LTC4 generation from murine bone marrow-derived mast cells stimulated by anti-IgE serum [144]. 

Several other cell types have also been shown to secrete histamine-releasing activity, some of which may be peptide in nature (although more work is necessary for a definitive characterization). For example, human lung macrophages cultured for 24 h have been shown to release a soluble factor (12 and 30 kDa) that stimulates isolated human lung mast cells and human basophils to release histamine [ 145]. The generation and release of this factor developed over time (> 1 h) and was blocked by cycloheximide, indicating that protein... 

Interleukin-1 (IL-1) produced by monocytes and several other cell types [70, 146] has a wide array of biological properties, including T cell activation and inflammatory interactions with muscle, liver, fibroblasts, brain and bone [70, 146], IL-1, both natural and recombinant, has been shown to release histamine from human basophils and from human adenoidal mast cells [70,146,151] and this release was abolished by an IL-1 antibody. However, the average release produced by 10 units of IL-1 was less than 20% and there was considerable variability between populations of basophils in the extent of histamine release. Moreover, the secretory response elicited was quite slow (within 15 min) compared with that of other peptides [151]. Desensitization of the basophils by anti-IgE serum had no effect on the subsequent IL-1 response, suggesting different mechanisms of action [ 151], as has been the case with other peptides. Interestingly, the portion of the IL-1 molecule that is responsible for its immu-nostimulatory activity appears to be separate from that portion responsible for its proinflammatory effects [152]. However, that portion of the molecule responsible for eliciting basophil and mast-cell histamine release has not as yet been defined. 

Bk has been shown to stimulate histamine release from isolated peritoneal rat mast cells [30, 87] and this secretory response, like that elicited by other peptides, requires a source of metabolic energy and is prevented by depletion of cellular Ca [30, 87]. The subsequent treatment of such cellular Ca-depleted mast cells with Bk produces an inactivation or desensitization phenomenon to the subsequent addition of extracellular Ca (secretion declines as the time... 

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.

Figure 4.10. Dose-relationships for histamine release from rat mast cells induced by a variety of peptides [99], No calcium was added to the extracellular medium. Each point is the mean of two or more determinations A, poly(L-lysine) (molecular weight 30.000-70,000) , succinylated poly(L-lysine) (molecular weight 30,000-70f)00) V, [n-Phe7 )SP , fD-Prcr2, D-Phe7, D-Trpv]SP, u , SP/ A, eledoisin-related peptide , eledoisin O, N-terminal tetrapeptide of substance P.

A clue as to why the cationic N-terminal region and the hydrophobic C-terminal portion of SP are required for full histamine-releasing activity comes from studies of the electrical conductivity of black lipid membranes in the presence of peptides. Using SP, these authors [176] concluded that SP probably binds by its N-terminal region to negatively charged sites on membrane lipids, while the C-terminal portion of the molecule penetrates the hydrophobic core of the lipid bilayer, which could induce an increase in membrane permeability or a slight alteration in membrane conformation. 

In addition to the necessity for basic amino acids at the N-terminal region in eliciting mast cell histamine release, a stereospecific component to peptide action has been demonstrated [167], When the core peptide of corticotropin,... 

Stimulation of mast cells by peptides [86a] or by compound 48/80 [86a, 200] is not accompanied by an increase in the methylation of membrane lipids. In contrast, IgE-dependent stimulation of the mast cell results in an increase in the methylation of specific membrane phospholipids [200, 201] and IgE-dependent stimulation of histamine release is inhibited by agents that block this enzymatic methylation [200, 201]. 

Some agents are bifunctional, causing the release of histamine and recruiting leukocytes. Bifunctional mediators include bacterial peptides, endotoxins, DNA, C3a, C5a and bradykinin. Each of these substances can exert dual effects. This may either occur directly, as in the case of bacterial peptides and bradykinin causing chemotaxis and bronchial smooth muscle contraction, or indirectly, as endotoxin and DNA conversion of complement. C3a and C5a act indirectly as complement fragments to effect histamine release, which in turn contracts bronchial smooth muscle. However, both appear to act directly to effect chemotaxis with C5a, the more potent fragment. 

Angioedema may be precipitated by histamine release but appears to be maintained by peptide kinins that are not affected by antihistaminic agents. For atopic dermatitis, antihistaminic drugs such as diphenhydramine are used mostly for their sedative side effect, which reduces awareness of itching. 

Mast cell degranulating peptide Enzymes Histamine release from mast cells... 

Peptides that present allergen-specific T-cell epitopes retain the ability to immuno-modulate T-cells, but less an ability to cross-link IgE and activate effectors cells. For example, synthetic peptides-based vaccine derived from major peanut allergen, Ara h 2 composed of thirty 20-mers that overlapped by 15 amino acids (Sicherer and Sampson 2007). Subcutaneous or intranasal administration of the vaccine reduced Ara h 2-specific IgE and plasma histamine release levels as well as anaphylactic symptoms scores in a murine model of peanut anaphylaxis. 

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. 

Mechanisms of itch are both peripheral and central. Impulses pass along the same nerve fibres as those of pain, but the sensation experienced differs qualitatively as well as quantitatively from pain. In the CNS endogenous opioid peptides are released and naloxone can relieve some cases of intractable itch. Local liberation of histamine and other autacoids... 

Cathelicidins and defensins induce histamine release from mast cells [182-184]. Human BD-2, -3 and -4 and a-defensins recruit monocytes, T cells (memory and naive) and immature dendritic cells [185-188] Cathelicidins (bovine, human, mouse and pig) are chemotactic for several subsets of peripheral blood cells in vitro [178,189] and in vivo [190]. For example, CRAMP (Cathelin-related antimicrobial peptide, the murine orthologue of human cathelicidin/LL-37), like LL-37, was chemotactic for human monocytes, neutrophils, macrophages, and for mouse peripheral blood leukocytes in vitro and in vivo [189]. These results suggest that host defense peptides recruit innate and adaptive immune cells for protective cellular and humoral responses to pathogens. 

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