The role of histamine in allergic disease: re‐appraisal of its inflammatory potential

Studies of allergic diseases, in particular asthma, rhinitis and urticaria, have suggested that histamine, a biogenic amine synthesized and stored mainly in mast cells and basophils, plays a prominent role in the pathophysiology of these diseases (1–3). Several immunologic and nonimmunologic stimuli, such as allergen, immunoglobulin (Ig)E, cytokines (interleukin (IL)-1, IL-3, IL-8, GM-CSF), substance P, complement C3a and C5a, platelet-activating factor (PAF), hyperosmolarity, physical stimuli (vibration, heat, cold), etc., induce the release of histamine from mast cells and basophils, following which it diffuses rapidly into the surrounding tissues and exerts its effects, before being metabolism and excreted in the urine (4). In experimental asthma induced by allergen or exercise challenge, it has been demonstrated that the levels of histamine are increased in the circulation and implicated in bronchoconstriction (5–7). Studies of symptomatic asthmatics have also demonstrated that histamine levels are significantly increased in the bronchoalveolar lavage (BAL) of these individuals, compared with histamine levels in BAL of asymptomatic asthmatics (8,9). Similarly, allergen challenge in patients with allergic rhinitis significantly increases the levels of histamine in nasal secretions of these individuals (10–12), implicating a role for this mediator in the pathophysiology of allergic rhinitis. Indeed, nasal challenge with histamine has been shown to induce nasal blockage, sneezing and rhinorrhoea (13,14), likely as a result of sensory nerve stimulation in the nasal mucosa (15). In patients with cold urticaria, challenge with ice-water leads to a rapid rise in plasma histamine concentration within 2 min, which peaks at 5 min and returns to baseline values by 15–30 min (16). Investigations of patients with chronic urticaria have also indicated that histamine is a central mediator in this allergic condition, with increased levels detected both in the lesions and normal skin of patients with urticaria, compared with skin of healthy individuals (17–19). Furthermore, the responsiveness of skin to histamine is also increased in patients with urticaria (19). Apart from the classical activities of histamine, there is an increasing body of evidence that histamine also elicits pro-inflammatory and immune-modulatory effects, which might be of pathophysiological relevance. The findings of histamine receptors expressed on a variety of immune and nonimmune cells suggest a much wider and more critical role of this mediator in allergic disease, than is considered presently. Consequently, it is likely that antihistamines have a wider impact on allergic inflammation, and that effects on immune cells which have been linked to nonreceptor mediated pathways so far, may actually be receptor-dependent. This review aims to give an overview on a currently emerging new understanding of the role of histamine in allergic disease. The effects of histamine arise from its interaction with one of at least three subclasses of specific histamine receptors, H1, H2 and H3 (20,21). The histamine receptors are G protein-coupled receptors located on various histamine responsive target tissues and cells. H1 receptors are preferentially stimulated by 2-methylhistamine, which results in the activation of phospholipase C and subsequently increased concentrations of the secondary messengers inositol-1,4,5-triphosphate (IP3) and intracellular calcium (20–23), involved in signal transduction and potentiation of specific biologic effects. In contrast, studies of H2 and H3 receptors have suggested that these are stimulated preferentially by 4-methylhistamine and (R/N)-α-methylhistamine, respectively. Activation of these receptors is also associated with increases in IP3 and intracellular calcium concentrations (20). The use of more recently developed molecular cloning techniques, however, has demonstrated that other novel histamine receptors are also expressed in addition to the classical H1, H2 and H3 receptors (24–26). Utilizing sequence analysis data from the human genomic database, Oda and colleagues (25) have cloned and characterized a novel orphan G-protein-coupled receptor, GPRv53. This receptor has the highest homology with the H3 receptor, among all the known G-protein-coupled receptors, and possesses histamine binding and receptor activating/inhibiting features similar to the H3 receptor. Analysis of tissues/cells expressing the GPRv53 receptor, however, suggests that this receptor is localized in peripheral blood leukocytes, spleen, thymus and colon, but not the brain, to which the expression of H3 receptor is restricted. These findings suggest that there may be heterogeneity within the H3 receptor. Similarly, Nakamura and colleagues have recently cloned the histamine H4 receptor (HH4R) from human leukocyte cDNA (26). These studies demonstrated that the HH4R receptor had about 40% amino acid sequence homology, compared with the H3 receptor, and like the GPRv53 receptor the HH4R receptor was also expressed in a variety of peripheral tissues, but not the brain. The specific function of these receptors is not clear and remains to be evaluated (Table 1). In allergic disease, the interaction of histamine with the histamine H1-receptor, mediates a variety of classical pathophysiological effects, including vascular permeability, smooth muscle contraction, vasodilatation and flushing, mucus secretion and pruritus, which either singly or in conjunction with one another lead to bronchial obstruction in asthma; nasal blockage, sneezing, itching and discharge in rhinitis; and itchy skin wheals/flares in urticaria (1,27). Histamine, acting via the H1 receptor is also an important neurotransmitter in the central nervous system (28). Although the activation of H2 receptors is primarily important in the augmentation of gastric acid secretion from parietal cells, it also contributes to increases in respiratory mucus secretion, nasal airways resistance and smooth muscle relaxation in the lower airways (20,27,29,30). In contrast, the H3 receptors have primarily been implicated in the autocrine regulation of histamine synthesis and release from nerve tissue (27). The demonstration that H3 receptors are expressed in postganglionic cholinergic nerves in human bronchi (31) has prompted the hypothesis that stimulation of these receptors may act as a protective mechanism against excessive bronchoconstriction. Although the classical effects of histamine, expressed at the organ level, are generally well documented and much emphasized in allergic disease, this is not the case for the increasing amount of evidence which suggests that histamine also directly or indirectly influences the activity of several inflammatory/effector/immunologic cell types involved in the pathogenesis of allergic disease. Consequently, it is likely that histamine plays a much wider and critical role as a pro-inflammatory mediator in allergic disease, than is considered presently. Indeed, several studies have demonstrated that histamine receptors are expressed on basophils, mast cells, neutrophils, eosinophils, lymphocytes, macrophages, epithelial cells and endothelial cells, and therefore is likely to modulate the function of these cells. Histamine receptor binding studies with specific receptor antagonists have demonstrated that basophils express predominantly H2 receptors and that these are involved in the regulation of IgE-induced histamine release, as indicated by enhanced histamine release in the presence of anti-IgE and cimetidine (a H2 receptor antagonist), but not in the presence of anti-IgE and thioperamide (a H3 receptor antagonist) (32–34). Studies of partially purified human conjunctival mast cells, which are thought to be similar to human connective tissue mast cells in their response to a variety of secretagogues, have indicated the expression of H1, H2 and H3 receptors, of which the H1 -receptors appear to be most active with respect to mediator release from these cells (35,36). Neutrophils have been shown to express H1 and H2 receptors (37,38). Functional studies have suggested that the effects of histamine on neutrophils are also mostly inhibitory and mediated via H2 receptors. Autologous serum-induced chemotaxis of neutrophils in normal and atopic subjects is inhibited by histamine in a dose-dependent manner in vitro, and this inhibition is more marked in atopic individuals (39). Furthermore, incubation of neutrophils from these individuals with cimetidine, but not promethazine, reverses the histamine-induced inhibition of neutrophil chemotaxis. Similarly, an in vivo study has demonstrated that administration of histamine by either infusion, subcutaneous injection or inhalation significantly decreased neutrophil chemotaxis in healthy volunteers (40). The effect of histamine inhalation was mimicked by inhalation of impromidine (H2 agonist), but not by betahistine (H1 agonist), and blocked by prior treatment with oral cimetidine. Other studies have demonstrated that histamine, acting via H2 receptor signalling, also inhibits the activation of neutrophils, as indicated by inhibition fMet-Leu-Phe induced superoxide (O2–) formation, degranulation and membrane potential changes (41,42). The inhibitory effects of histamine and H2 agonists could be reversed by treatment with cimetidine. Eosinophils also express H1 and H2 receptors, and in contrast to the inhibitory effect of histamine on basophils and neutrophils, the in vitro effect of histamine on eosinophils is generally stimulatory, at lower concentrations. Clark and colleagues (43) have demonstrated that while preincubation of eosinophils with 10−5M or higher concentrations of histamine inhibited the chemotactic response of eosinophils to endotoxin-activated serum (C5a), preincubation of eosinophils with a lower concentration of 10−6M histamine had the opposite effect, augmenting the C5a-stimulated eosinophil chemotaxis. Furthermore, H2 and H1 receptor antagonists, respectively, blocked these effects. The expression of a novel H3 receptor, which may mediate the direct eosinophil chemotactic response towards histamine has also been reported (44). Although this receptor appears to have similar antagonist binding properties to those observed for the H3 receptor found in the central nervous system (CNS), it does not bind (R/N)-α-methylhistamine with the same potency as histamine, suggesting differences between the characteristics and function of H3 receptors expressed in CNS and on the eosinophil. Other studies have demonstrated that histamine, acting via the H1 receptor, also enhances eosinophil C3b receptor expression (45,46), a mechanism that may be of importance in the amplification of complement-dependent parasite killing. However, in a recent study, 0.1–50 µM histamine was shown to inhibit eosinophil degranulation, as indicted by decreased release of C5a-mediated eosinophil peroxidase (EPO) (47). This study also demonstrated that selective H2 receptor agonists produced an effect similar to that shown by histamine and that cimetidine, the H2 receptor antagonist reversed this inhibitory effect of histamine. In contrast, treatment with neither mepyramine nor thioperamide (H1 and H3 receptor antagonists, respectively) significantly inhibited the C5a-induced release of EPO from eosinophils, suggesting the pivotal role of H2 receptors in this respect. An association between histamine and eosinophil activity in allergic disease has also been demonstrated in vivo in patients with allergic rhinitis undergoing segmental allergen challenge, followed by airway sampling by BAL after 5 min and 48 h (48). Peripheral blood maximal histamine release in response to in vitro antigen challenge was also determined in each patient before segmental bronchoprovocation. The number of eosinophils in BAL samples collected after 48 h, in particular, were significantly increased and correlated with the maximal basophil histamine release noted for each individual, suggesting a direct causal relationship between basophilic mediator release and airway eosinophilia (Fig. 1). Correlation between histamine release and proportion of eosinophils in bronchoalveolar lavage (BAL) fluid obtained 48 h after antigen segmental bronchial provocation (r = 0.67, P < 0.0001, n = 34, Spearman's Rank test). (from Jarjour NN et al. 1997 –[47;] reprinted with permission). Numerous studies on the expression of histamine receptors on lymphocytes and the effects mediated through these receptors have been published and more recently reviewed by Sachs and colleagues (49). These authors concluded that both H1 and H2 receptors are present on the lymphocytes, and although there are few data with respect to the functional significance of the H1 receptors and the distribution of H2 receptors on different lymphocyte subsets, in general signalling via the H1 receptor was associated with enhancement and signalling via the H2 receptor with inhibition of lymphocyte responses. More recently, Jutel and colleagues (50) have demonstrated that Th1 and Th2 cells express distinct surface histamine receptor patterns (Th1 cells express predominantly H1 receptors and Th2 cells express predominantly H2 receptors), and that histamine enhances Th1-type responses and negatively regulates Th2-type responses, as indicated by increased release of tumour necrosis factor (TNF)-α and decreased release of IL-4 and IL-13, respectively. Furthermore, the differential response of these cells to histamine is a result of the type of intracellular signals generated by histamine stimulation. Whilst H1 receptor signalling involves calcium-dependent phospholipase activation and generation of IP3, H2 receptor signalling involves adenylate cyclase activation and cAMP formation. A receptor binding study of human peripheral blood lymphocytes has demonstrated that histamine trifluoromethyl-toludine (HTMT) derivative lead to a two-phase increase in intracellular calcium and an increase in inositol phosphate production, of which the increase in calcium was competitively antagonized by high concentrations of histamine, but not by any of the classical H1, H2 or H3 receptor antagonists (51). These results suggest that there may be a specific binding site for HTMT on lymphocytes that is different to the three classic histamine receptors. Although, several functional studies suggest that histamine primarily modulates T-suppressor activity [e.g., delayed type hypersensitivity, cytotoxic T-lymphocyte-mediated target cell killing, cell-mediated lympholysis, and natural killer activity] via H2 receptor signalling (52), some studies suggest that stimulation of the H2 receptors may also indirectly enhance the allergic cascade. It has been demonstrated that 10−6-10−4M histamine inhibited Staphylococcal Enterotoxin A-induced synthesis of interferon (IFN)-γ and IL-2 and that these effects were reversed by treatment with cimetidine, but not by treatment with diphenhydramine (53). More recent studies have confirmed this finding by demonstrating that histamine inhibited lipopolysaccharide (LPS)-induced IFN-γ-gene expression from human peripheral blood mononuclear cells (PBMC) (54) and IFN-γ cytokine release human CD4+ T-cell clones, classified as either Th0, Th1 or Th2 on the basis of their IL-4 and IFN-γ secretion patterns (55). Histamine-induced inhibition of IFN-γ release was noted in Th1 clones, but not Th2 clones, and this effect was reversed by a H2, but not H1 or H3, receptor antagonists. Furthermore, histamine has also been shown to directly increase the synthesis of the pro-inflammatory cytokines IL-1 β and IL-6 by lymphocytes, and anti-CD23- and anti-CD28-induced release of IL-4 and IL-5, but not IL-2 or IFN, from T cells can be inhibited by treatment with terfenadine (49). Similarly, other studies have demonstrated that histamine leads to synthesis and release of a lymphocyte chemoattractant factor (LCF) from H2 receptor bearing lymphocytes and to the release of two distinct types of lymphocyte migration inhibitory factors (LyMIFs) from a subset of only H1 receptor bearing lymphocytes (56,57). It has been speculated that the production of LyMIFs resulting from lymphocyte H1 receptor signalling may contribute to immobilization of effector T lymphocytes chemokinetically attracted to certain inflammatory sites, with subsequent exacerbation of inflammation. Although there are comparatively few reports, some recent studies have demonstrated the presence of H1 and H2 histamine receptors on human monocytes and macrophages (58–61), suggesting that histamine may also modulate the activity of these cells in allergic disease. Indeed, differentiation of monocytes into macrophages leads to switching from H2 to H1 histamine receptors (58,60). Furthermore, histamine-induced H1 receptor signalling induces the release of pro-inflammatory compounds such as TNF-α (58), prostaglandin D2 (PGD2 59), and β-glucuronidase (61). Cultured human bronchial epithelial cells express active H1 and H2 receptors, as indicated by histamine-induced generation of and respectively, and of and cAMP release by treatment with and The expression of H1 receptors has also recently been demonstrated on human nasal and epithelial cells, suggesting that histamine may the activity of these cells as Indeed, the role of epithelial cells as of inflammation, in allergic airway disease, has been the of much have documented that bronchial and nasal epithelial cells can and release a variety of active acid cell and that the activation function of both inflammatory and cells involved in the pathophysiology of asthma and allergic rhinitis An study of the effects of histamine on mediator release from human bronchial epithelial cells that H1 receptor activation with 2 histamine to of phospholipase production of activation of the factor and expression of Histamine-induced increase in was inhibited by incubation of the cells with specific and while expression of was inhibited by and and suggesting a of histamine-induced inflammatory within the Similarly, studies in human epithelial cells have demonstrated that histamine stimulated the release of and from these cells in a dose-dependent manner at concentrations = and that several H1 receptor antagonists, but not (H2 antagonist) or thioperamide antagonist), inhibited this cytokine release In one study, increased expression of and was noted on bronchial epithelial cells following treatment with histamine In of the of endothelial cells at the the of these cells to the pathophysiology of allergic disease has been The of endothelial cells that contribute to the pathophysiology associated with airway inflammation, in particular, can be classified of endothelial and production of expression of as and and leukocyte as IL-8, and leukocyte and within the blood and with vascular changes results in increased plasma and migration of the to the site of in the The effect of histamine on vascular has been well documented and is a of H1 receptor signalling, which results in the of of the endothelial and subsequent of in the and of In vitro studies have demonstrated that active H1 H2 receptors are expressed on human endothelial cells present in a variety of tissues, including the airway and of which human endothelial cells have been the most in likely as a of comparatively and to these cells. A recent study has indicated that histamine regulates the expression of histamine receptor on endothelial cells and therefore influences the inflammatory response in allergic disease The levels of for both the H1 and H2 receptors were by histamine, of which the effect on H2 receptor was rapid and compared with a and effect on the H1 receptor the H2 receptor was mainly as a result of H1 receptor Histamine-induced receptor signalling on the endothelial cells also directly modulates inflammatory changes in these cells. of with or 10−5M histamine results in the release of neutrophil chemoattractant activity from these cells, an effect blocked by cimetidine, but not diphenhydramine Histamine also leads to a of neutrophil to these which is mimicked by H1 and H2 receptors H3 agonists not appear to have any effect A of the signal transduction suggests that either histamine or H1 or H2 of neutrophils to endothelial cells involves activation of phospholipase and inhibition of these with specific can significantly this Activation of adenylate however, neutrophil Histamine also eosinophil to by directly and augmenting IL-4 and expression of on the In contrast to neutrophil eosinophil appears to be by signalling via H1 and H3 receptors, mepyramine and but not cimetidine, inhibited the histamine-induced expression on (Fig. histamine receptor antagonists inhibit expression in tumour necrosis factor (from et al. reprinted with permission). the of such data in several studies have demonstrated that of the with histamine induces leukocyte and in The effect of histamine is mediated via both H1 and H2 receptor signalling and of on endothelial cells in the It is clear that inflammation, histamine is from basophils and mast cells and contributes to the of inflammatory either by or inflammatory on its concentration and stimulation of either the H1 or H2 receptor suggests that concentrations of histamine acting via H1 receptors appear to have effects on inflammatory cells, as high concentrations acting via the H2 receptors have an inhibitory Indeed, on some experimental an hypothesis that airway to histamine in asthmatics was to an of histamine H2 receptors on and airway smooth or a of histamine and in the airways However, with to the pathophysiology of allergic disease, it is that histamine directly enhances the activity of eosinophils, Th2 lymphocytes, macrophages, epithelial and endothelial cells, all of which are known to a role in allergic inflammation. In contrast, histamine inhibits the activity of basophils and neutrophils, and the release of IFN-γ and IL-2 from Th1 clones, but not Th2 in of the effector cell function of eosinophils and Th2 lymphocytes in allergic diseases, it is likely that histamine plays a more prominent pro-inflammatory role than is In of the evidence of both direct and effects of histamine on cells, it is likely that of the reported effects of the generation antihistamines actually result as a of their effects at the H1 receptor, than at some receptors, as has been speculated by some It has been suggested that in of the and generally of of the effects observed with these compounds are and result from an association with cell decreased and inhibition of membrane associated than from and of H1 receptor Furthermore, of the effects of the of these effects has been mostly of these effects have been demonstrated in vitro at high concentrations of the compounds and also there are comparatively few studies a between and specific effects However, a recent by has the and of the effects of antihistamines in of more recent Studies in cells have shown that expression of the human histamine results in an activation of the the secondary IP3 and that this histamine receptor activity can be decreased by treatment with several It has been suggested that this of the histamine as an between its and active the antihistamines can histamine it is likely that these compounds act as agonists which with and the of the receptor the towards the active than antagonists. Furthermore, activation has been shown to result in activation in cells, and concentrations of some can the expression of this factor in with the generation of a variety of pro-inflammatory cytokines IL-8, TNF-α and GM-CSF), it is likely that the antihistamines their effects by both and with the are likely to higher concentrations of the antihistamines in to effects. Whilst the effects of antihistamines are to be as a of the for high it has been suggested that the effects of the antihistamines may actually be although not as marked as the effects for Indeed, there is some evidence of an association between and effects of an in patients with allergic rhinitis treatment was from the one of treatment to that of treatment In a study of to or treatment with an for was also shown to significantly the of asthma, compared with studies are to the involved in expressing the effects of antihistamines in to a understanding of the for this of compounds and their use in the of allergic disease.