Sesha Reddigari

Histamine releasing factors and cytokine-dependent activation of basophils and mast cells

Publisher Summary This chapter describes the various types of histamine releasing factors (HRFs), discusses their interaction with basophils or mast cells, and speculates regarding their role in inflammation in general, and in allergic diseases in particular. The release of histamine from human basophils or mast cells is typically initiated by the interaction of antigen with surface-bound immunoglobulin (IgE) antibody. Histamine releasing factors are defined as products of activated cells that interact with basophils and mast cells to cause the release of histamine. Two general types of HRFs is described, one whose function appears to be dependent upon cell surface IgE and others that are IgE independent. A variety of reports confirmed that lymphoid cells produce such a factor, and HRF-like activities are described as products of T lymphocytes, mixed mononuclear cells, alveolar macrophages, platelets, B lymphocytes, and neutrophils. Such activity also appeared to be present in nasal washings of allergic subjects and in antigen-challenged cutaneous late-phase reactions. Histamine releasing factors cause a noncytotoxic granule exocytosis from basophils when assessed by electron microscopy and cause histamine release as well as release of lipid mediators such as leukotriene C4.

Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions

Contact activation occurs when plasma comes in contact with negatively charged man‐made surfaces but no substance that initiates contact activation in vivo has been identified. We have isolated a mast cell heparin proteoglycan (MC‐HepPG) from a Furth mouse mastocytoma‐derived cell line that is analogous to human tissue‐type mast cell HepPG. This material and other glycosaminoglycans (GAGs) were tested for their ability to accelerate the reciprocal activation of factor XII and prekallikrein and the autoactivation of factor XII. Quantitative analysis showed the MC‐HepPG to be as active as dextran sulfate on a weight basis; hog intestine heparin, dermatan sulfate. keratan polysulfate and chondroitin sulfate C were less active, other sulfated polysaccharides were essentially inactive. Incubation of MC‐HepPG in 1:4 diluted plasma resulted in complete cleavage of high molecular weight kininogen in a factor Xll‐dependent reaction. All of the MC‐HepPG dependent reactions described above were inhibited by preincubation of MC‐HepPG with heparinase I and II but not by pretreatment with heparitinase. chondroitinase ABC or the serine protease inhibitor aPMSF thus indicating that heparin proteoglycan is indeed acting as an initiating ‘surface’. We analysed the proteoglycan preparation by HPLC gel filtration. Fractions spanning a molecular weight range of > 400000–8000 were active initiators. Comparison of the chromatograms obtained before and after cleavage of GAG side chains from the protein core suggested that dissociated GAGs in the MW range 69000–17000 are the most active species rather than the complete proteoglycan. MC‐HepPG GAGs therefore represent a physiologic macromolecule with activity comparable to non‐physiological surfaces in a purified system and with the capability to induce activation of the contact system in diluted plasma. Its ability to promote kinin generation links cellular and humoral inflammatory responses in the perivasculature and provides a possible explanation for the elevated kinin levels observed after allergen exposure.

Quantification of human high molecular weight kininogen by immunoblotting with a monoclonal anti-light chain antibody.

Activation of the Hageman factor-dependent pathways in human plasma leads to the cleavage of high molecular weight kininogen (HMWK) into a disulfide-linked two-chain (heavy and light chain) molecule and release of bradykinin, a vasoactive peptide. We have utilized murine monoclonal antibodies to the light chain of HMWK (Blood (1988) 71, 1344) and developed a very sensitive immunoblotting assay to detect and quantify the amount of cleaved or uncleaved HMWK in whole plasma. The total HMWK content of plasma from apparently healthy donors was 55 micrograms/ml by this method. Cleaved HMWK was detected when only 2% of the plasma had been activated and the method was sensitive down to 2 ng of HMWK. Because of the extreme lability of bradykinin in body fluids, quantification of cleaved HMWK provides an important adjunct which reflects contact activation and permits calculation of a theoretical upper limit of the potential kinin formed.

Chemokines and the allergic response

Abstract The β subfamily of chemokines contains‐cytokine‐like factors which are chemotactic for human basophils and eosinophils. They also stimulate these cells to secrete pro‐inflammatory substances such as histamine or eosinophil cationic protein. MCAF/MCP‐1, MCP‐2, MCP‐3, RANTES and MIP‐lα all attract and stimulate basophils; MCP‐I and MCP‐3 are the most potent. RANTES, MCP‐3 and to a lesser degree MIP‐Ia are chemotactic factors and activators of eosinophils. Cytokines such as IL3, IL5 and GM CSF can augment the responses of these cells to the various chemokines and function as primers. These substances may have particular importance as mediators of allergic inflammation, particularly the late phase component of the response.

Effect of neurotropin® on the activation of the plasma kallikrein-kinin system

Bradykinin (BK), an important mediator of allergic reactions and pain induction, is released by the activation of the plasma kallikrein-kinin (K-K) cascade. Neurotropin is a biological material obtained from inflamed rabbit skin inoculated with vaccinia virus and is widely used clinically in Japan as an effective agent for these disorders. Since its mechanism of action is not clearly known, we have investigated the effects of Neurotropin on the human plasma K-K system. In dextran sulfate-activated plasma, Neurotropin inhibited the formation of BK, the cleavage of high molecular weight kininogen (HK) and the formation of kallikrein-C1 inhibitor and activated coagulation factor XII (FXIIa)-C1 inhibitor complexes. Experiments using purified enzyme of the K-K cascade indicated that Neurotropin inhibited surface-mediated activation of coagulation factor XII (FXII) and the activation of prekallikrein by FXIIa. Neurotropin also inhibited the binding of FXII and HK to the activating surface. These data suggest that the ameliorating effects of Neurotropin in allergic disorders and pain syndromes may be related to this ability to inhibit activation of the K-K cascade and consequently the formation of BK.

Chemokines of the α, β-subclass inhibit human basophils' responsiveness to monocyte chemotactic and activating factor/monocyte chemoattractant protein-1

Abstract Monocyte chemotactic and activating factor (MCAF) is the most potent cytokine that activates basophils to release histamine. The response of human basophils to either simultaneous or sequential addition of the chemokines RANTES, macrophage inflammatory protein (MIP)-1α, MIP-1β, platelet factor (PF)4, connective tissue activating peptide III (CTAP-III), interleukin (IL)-8, and inflammatory protein (IP)-10 on MCAF-induced histamine release was studied. Simultaneous addition of MCAF and any of the chemokines studied evoked an augmented response as measured by histamine release, whereas preincubation of leukocytes or purified basophils (80%) with these chemokines decreased MCAF-induced histamine release in a dose-dependent manner. Histamine release by anti-IgE remained unchanged. When tested at 5 × 10 -9 mol/L, the decrease in histamine release by RANTES was 69.2% ± 3.5%, by MIP-1α 48.8% ± 3.1%, by MIP-1β 42.9% ± 3.1%, by PF4 56.5% ± 2.9%, by IL-8 41.2% ± 2.2, by CTAP III 27% ± 4.4%, and by IP-10 15.3% ± 2.6%. The peak inhibition of histamine release by the chemokines was reached within 10 minutes of preincubation with basophils and remained unchanged thereafter. Washing basophils after preincubation with chemokines abolished the inhibition, with the exception of desensitization by low concentrations of MCAF. With the exclusion of MCAF and RANTES, none of the chemokines (at the concentration range of 5 × 10 -8 to 5 × 10 -11 ) induced significant (>10% above spontaneous) histamine release from basophils. Preincubation of basophils with C5a (5 × 10 -10 mol/L) did not affect histamine release, whereas preincubation with granulocyte-macrophage colony-stimulating factor (10 ng/ml) or IL-5 (10 ng/ml) enhanced MCAF-induced histamine release by 121.8% ± 10.1% and 108% ± 10.8%, respectively. We have therefore characterized RANTES, MIP-1α, MIP-1β, CTAP III, PF4, IL-8, and IP-10 as inhibitors of MCAF-induced histamine release. Although the results are consistent with receptor blockade, the α and β chemokines appear to interact with separate receptors linked to G proteins; thus, a mechanism of receptor class desensitization is proposed. Interaction of this group of cytokines at the site of allergic inflammation may modulate a function of basophils to initiate, augment, or inhibit histamine release. (J ALLERGY CLIN IMMUNOL 1995;95:574-86.)

Activation of the plasma kinin forming cascade along cell surfaces

Proteins of the plasma kinin-forming cascade bind to endothelial cells and activation of the cascade can be initiated along the surface. The light chain of high molecular weight kininogen (HK) (domain 5) and factor XII bind to gC1qR, the heavy chain of HK (domain 3) binds to cytokeratin 1 and the interactions are zinc dependent. Prekallikrein binds to domain 6 of HK. Antisera to gC1qR and cytokeratin 1 inhibit binding and activation. Incubation of normal plasma with endothelial cells leads to gradual conversion of prekallikrein to kallikrein, while plasma deficient in factor XII or HK are inactive within a 2-hour time frame. Thus factor XII is critical for activation to proceed. Augmentation of these reactions may occur when C1 inhibitor is functionally deficient or with ACE inhibitors which also inhibit kininases.

Histamine-Releasing Factors

Histamine-releasing factors (HRF) are cell-derived products which cause histamine release from basophils and/or mast cells. We have isolated HRF from human mononuclear cells and platelets and have purified 3 molecular species having molecular weights of 8-10, 15-17 and 35-41 kilodaltons (kDa). We prepared monoclonal antibodies to the 8- to 10-kDa form and have isolated it by affinity chromatography. A broad band was seen upon sodium dodecyl sulfate gel electrophoresis in 15% gels as well as immunoblotting, and the band was divided into an upper and a lower half. Amino acid sequence analysis of the upper half indicated that it is closely homologous to connective-tissue activating peptide III (CTAP III). The lower half also aligned with CTAP III beginning with amino acid 16; thus, proteolysis and occurred removing the N-terminal 15 amino acids. This corresponds to neutrophil-activating peptide 2. Both appear to be active on basophils with a dose-response between 250 ng up to 10 micrograms. Although interleukin-3 and granulocyte/macrophage-colony-stimulating factor have similar histamine-releasing capability at lower effective concentrations, they do not account for HRF activity in mononuclear cell/platelet supernatants, and the 15- to 17 and 40- to 41-kDa moieties appear to be unique gene products unrelated to previously described cytokines.

Assembly of the Human Plasma Kinin-Forming Cascade along the Surface of Vascular Endothelial Cells

The generation of bradykinin by contact activation requires autoactivation of factor XII (Hageman factor) upon initiating surfaces, conversion of prekallikrein to kallikrein, and digestion of high-molecular-weight (HMW) kininogen. Endothelial cells have a high-affinity receptor that binds either HMW kininogen or factor XII in a zinc-dependent interaction, and activation of factor XII can occur along this surface to initiate kinin formation. Tissue injury, exposure of proteoglycans, or release of mast cell heparin will markedly accelerate these reactions. The bradykinin released binds to endothelial cell B-2 receptors along the inner surface of blood vessels which results in dilatation and increased vascular permeability.

Further characterization of histamine releasing chemokines present in fractionated supernatants derived from human mononuclear cells

Background Histamine releasing factors (HRF) are members of the β chemokine family of cytokines and have been characterized using recombinant proteins. Mononuelcar cell and/or platelet supernatants have been shown to contain HRF and the initial void peak obtained using Mono Q anion exchange chromatography possesses such activity, as do two later peaks eluted from the column.