Histamine Articles 3

© 2012

Histamine in the immune regulation of allergic inflammation

         (Akdis and Blaser 2003) Download

Histamine was the first mediator implicated in mechanisms of allergy, asthma, and anaphylactic shock because it has been discovered to mimic several features of these diseases. In addition to its well-characterized effects in the acute inflammatory and allergic responses, it was recently demonstrated that histamine regulates several essential events in the immune response. Histamine affects the maturation of immune system cells and alters their activation, polarization, chemotaxis, and effector functions. Histamine also regulates antigen-specific T(H)1 and T(H)2 cells, as well as related antibody isotype responses. Histamine binds to 4 different G protein-coupled receptors that transduce signals to cells through distinct pathways. The expression of these receptors on different cells and cell subsets is regulated, and apparently, the diverse effects of histamine on immune regulation are due to differential expression of 4 histamine receptors and their distinct intracellular signals. This article highlights novel discoveries in histamine immunobiology and discusses clinical findings or disease models that indicate immune regulation by histamine.

The vaso-dilator action of histamine, and its physiological significance

         (Burn and Dale 1926) Download

Histamine plays an essential regulatory role in lung inflammation and protective immunity in the acute phase of Mycobacterium tuberculosis infection

            (Carlos, Fremond et al. 2009) Download

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.

Physiological and clinical significance of enterochromaffin-like cell activation in the regulation of gastric acid secretion

            (Cui and Waldum 2007) Download

Gastric acid plays an important role in digesting food (especially protein), iron absorption, and destroying swallowed micro-organisms. H+ is secreted by the oxyntic parietal cells and its secretion is regulated by endocrine, neurocrine and paracrine mechanisms. Gastrin released from the antral G cell is the principal physiological stimulus of gastric acid secretion. Activation of the enterochromaffin-like (ECL) cell is accepted as the main source of histamine participating in the regulation of acid secretion and is functionally and trophically controlled by gastrin, which is mediated by gastrin/CCK-2 receptors expressed on the ECL cell. However, long-term hypergastrinemia will induce ECL cell hyperplasia and probably carcinoids. Clinically, potent inhibitors of acid secretion have been prescribed widely to patients with acid-related disorders. Long-term potent acid inhibition evokes a marked increase in plasma gastrin levels, leading to enlargement of oxyntic mucosa with ECL cell hyperplasia. Accordingly, the induction of ECL cell hyperplasia and carcinoids remains a topic of considerable concern, especially in long-term use. In addition, the activation of ECL cells also induces another clinical concern, i.e., rebound acid hypersecretion after acid inhibition. Recent experimental and clinical findings indicate that the activation of ECL cells plays a critical role both physiologically and clinically in the regulation of gastric acid secretion.

Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors

            (Elenkov, Webster et al. 1998) Download

IL-12 and IL-10, respectively, stimulate Th1 and Th2 immune responses. The development of some allergic reactions, infections, and tumors are associated with excessive histamine production and a shift toward Th2 responses. Here we address the possibility that this association is causally linked, at least in part, to modulation of IL-12 and IL-10 production by histamine. We report that histamine dose-dependently inhibited the secretion of human IL-12 (p70) and increased the production of IL-10 in LPS-stimulated whole blood cultures. These effects of histamine were antagonized by cimetidine, an H2 receptor antagonist, but not by selective H1 and H3 receptor blockers, and were mimicked by an H2 receptor agonist. The effects of histamine on IL-12 and IL-10 secretion were independent of endogenous secretion of IL-10 or exogenous addition of IL-12, while Ro 20-1724, a phosphodiesterase inhibitor, potentiated the effects of histamine on IL-12 and IL-10 production, implicating cAMP in its actions. Similar modulatory effects of histamine on IL-12 and IL-10 production, which were reversed by the H2 antagonist cimetidine, were observed in PBMC and isolated monocytes stimulated by Staphylococcus aureus Cowan strain 1 and LPS, respectively. Thus, histamine, via stimulation of H2 receptors on peripheral monocytes and subsequent elevation of cAMP, suppresses IL-12 and stimulates IL-10 secretion, changes that may result in a shift of Th1/Th2 balance toward Th2-dominance. This may represent a novel mechanism by which excessive secretion of histamine potentiates Th2-mediated allergic reactions and contributes to the development of certain infections and tumors normally eliminated by Th1-dependent immune mechanisms.

Histamine modulates microglia function

         (Ferreira, Santos et al. 2012) Download

ABSTRACT: BACKGROUND: Histamine is commonly acknowledged as an inflammatory mediator in peripheral tissues, leaving its role in brain immune responses scarcely studied. Therefore, our aim was to uncover the cellular and molecular mechanisms elicited by this molecule and its receptors in microglia-induced inflammation by evaluating cell migration and inflammatory mediator release. METHODS: Firstly, we detected the expression of all known histamine receptor subtypes (H1R, H2R, H3R and H4R), using a murine microglial cell line and primary microglia cell cultures from rat cortex, by real-time PCR analysis, immunocytochemistry and Western blotting. Then, we evaluated the role of histamine in microglial cell motility by performing scratch wound assays. Results were further confirmed using murine cortex explants. Finally, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) levels were evaluated by ELISA measurements to determine the role of histamine on the release of these inflammatory mediators. RESULTS: After 12 h of treatment, 100 muM histamine and 10 mug/ml histamine-loaded poly (lactic-co-glycolic acid) microparticles significantly stimulated microglia motility via H4R activation. In addition, migration involves alpha5beta1 integrins, and p38 and Akt signaling pathways. Migration of microglial cells was also enhanced in the presence of lipopolysaccharide (LPS, 100 ng/ml), used as a positive control. Importantly, histamine inhibited LPS-stimulated migration via H4R activation. Histamine or H4R agonist also inhibited LPS-induced IL-1beta release in both N9 microglia cell line and hippocampal organotypic slice cultures. CONCLUSIONS: To our knowledge, we are the first to show a dual role of histamine in the modulation of microglial inflammatory responses. Altogether, our data suggest that histamine per se triggers microglia motility, whereas histamine impedes LPS-induced microglia migration and IL-1beta release. This last datum assigns a new putative anti-inflammatory role for histamine, acting via H4R to restrain exacerbated microglial responses under inflammatory challenge, which could have strong repercussions in the treatment of CNS disorders accompanied by microglia-derived inflammation.

Gastric cancer: animal studies on the risk of hypoacidity and hypergastrinemia

            (Fossmark, Qvigstad et al. 2008) Download

Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.

Histamine-releasing factors and inhibitors: historical perspectives and possible implications in human illness

            (Grant, Alam et al. 1991) Download

The initiation of allergic reactions with the bridging of surface-bound IgE antibodies on mast cells and basophils by allergens is well recognized. However, it is clear that other factors most likely play a role in regulating these cells. A number of cytokines have been identified that modulate the secretory response of mast cells and basophils. Among the well-characterized cytokines, interleukin-3 and connective tissue-activating peptide III (or its degradation product, neutrophil-activating peptide 2) can increase the secretory response, whereas interleukin-8 specifically inhibits the response to cytokines. Additional factors are currently under investigation. Preliminary studies suggest an important role for these histamine-releasing factors in atopic disorders, as well as in other conditions in which an IgE-dependent mechanism is not demonstrable. Furthermore, these cytokines may modulate the response of basophils and mast cells in physiologic conditions, such as tissue repair and host defense.

Ischemia of rat stomach mobilizes ECL cell histamine

            (Kitano, Bernsand et al. 2005) Download

Microdialysis was used to study how ischemia-evoked gastric mucosal injury affects rat stomach histamine, which resides in enterochromaffin-like (ECL) cells and mast cells. A microdialysis probe was inserted into the gastric submucosa, and the celiac artery was clamped (30 min), followed by removal of the clamp. Microdialysate histamine was determined by enzyme-linked immunosorbent assay. In addition, we studied the long-term effects of ischemia on the oxyntic mucosal histidine decarboxylase activity in omeprazole-treated rats. Gastric mucosal lesions induced by the ischemia were enlarged on removal of the clamp. The microdialysate histamine concentration increased immediately on clamping (50-fold rise within 30 min) and declined promptly after the clamp was removed. In contrast, histidine decarboxylase activity of the ECL cells was lowered by the ischemia and returned to preischemic values 9 days later. Mast cell-deficient rats responded to ischemia-reperfusion much like wild-type rats with respect to histamine mobilization. Pretreatment with the irreversible inhibitor of histidine decarboxylase, alpha-fluoromethylhistidine, which is known to eliminate histamine from ECL cells, prevented the rise in microdialysate histamine. Pharmacological blockade of acid secretion (cimetidine or omeprazole) prevented the lesions induced by ischemia-reperfusion insult but not the mobilization of histamine. In conclusion, ischemia of the celiac artery mobilizes large amounts of histamine from ECL cells, which occurs independently of the gross mucosal lesions. The prompt reduction of the mucosal histidine decarboxylase activity in response to ischemia probably reflects ECL cell damage. The lesions develop not because of mobilization of histamine per se but because of ischemia plus reperfusion plus gastric acid.

Histamine and betahistine in the treatment of vertigo: elucidation of mechanisms of action

            (Lacour and Sterkers 2001) Download

The aim of this review is to provide clinicians with a picture of the mechanisms by which: histamine and histaminergic agonists act on the vestibular system both peripherally and centrally; and histaminergic agonists and antagonists interfere with the recovery process after peripheral vestibular lesion. We have focused on betahistine, a structural analogue of histamine with weak histamine H(1) receptor agonist and more potent H(3) receptor antagonist properties, to review the currently available data on the role of the histaminergic system in the recovery process after peripheral vestibular deficits and the effects of histamine analogues in the clinical treatment of vertigo. This review provides new insights into the basic mechanisms by which betahistine improves vestibular compensation in animal models of unilateral vestibular dysfunction, and elucidates particularly the mechanisms of action of this substance at the level of the CNS. It is proposed that betahistine may reduce peripherally the asymmetric functioning of the sensory vestibular organs in addition to increasing vestibulocochlear blood flow by antagonising local H(3) heteroreceptors. Betahistine acts centrally by enhancing histamine synthesis within tuberomammillary nuclei of the posterior hypothalamus and histamine release within vestibular nuclei through antagonism of H(3) autoreceptors. This mechanism, together with less specific effects of betahistine on alertness regulation through cerebral H(1) receptors, should promote and facilitate central vestibular compensation. Elucidation of the mechanisms of action of betahistine is of particular interest for the treatment of vestibular and cochlear disorders and vertigo.

Fasting-induced changes in ECL cell gene expression

         (Lambrecht, Yakubov et al. 2007) Download

Gastric enterochromaffin-like (ECL) cells release histamine in response to food because of elevation of gastrin and neural release of pituitary adenylate cyclase-activating peptide (PACAP). Acid secretion is at a basal level in the absence of food but is rapidly stimulated with feeding. Rats fasted for 24 h showed a significant decrease of mucosal histamine despite steady-state expression of the histamine-synthesizing enzyme histidine decarboxylase (HDC). Comparative transcriptomal analysis using gene expression oligonucleotide microarrays of 95% pure ECL cells from fed and 24-h fasted rats, thereby eliminating mRNA contamination from other gastric mucosal cell types, identified significantly increased gene expression of the enzymes histidase and urocanase catabolizing the HDC substrate L-histidine but significantly decreased expression of the cellular L-histidine uptake transporter SN2 and of the vesicular monoamine transporter 2 (VMAT-2) responsible for histamine uptake into secretory vesicles. This was confirmed by reverse transcriptase-quantitative polymerase chain reaction of gastric fundic mucosal samples from fed and 24-h fasted rats. The decrease of VMAT-2 gene expression was also shown by a decrease in VMAT-2 protein content in protein extracts from fed and 24-h fasted rats compared with equal amounts of HDC protein and Na-K-ATPase alpha(1)-subunit protein content. These results indicate that rat gastric ECL cells regulate their histamine content during 24-h fasting not by a change in HDC gene or protein expression but by regulation of substrate concentration for HDC and a decreased histamine secretory pool.

Inhibition of human primary melanoma cell proliferation by histamine is enhanced by interleukin-6

         (Lazar-Molnar, Hegyesi et al. 2002) Download

BACKGROUND: Interleukin-6 (IL-6) is a bifunctional growth factor in malignant melanoma; its expression increases during the malignant progression of the disease. Histamine, detected in large amounts in normal and pathological proliferating tissues, is an important paracrine and autocrine regulator of normal and tumour cell proliferation as well. MATERIALS AND METHODS: We investigated the presence and function of IL-6 and histamine in the WM35 primary human melanoma cell line with respect to their direct role in cell proliferation and their regulatory interactions. RESULTS: IL-6 inhibited the proliferation of WM35 melanoma cells and increased significantly the expression of histidine decarboxylase as well as histamine production. It had dose-dependent effects on the proliferation: high concentration (10-5 M) was inhibitory through H1 histamine receptors while low histamine concentration acting on H2 receptors, with a simultaneous increase of cAMP, enhanced colony formation in the monolayer. Furthermore, IL-6 increased the H1- but decreased the H2-histamine receptor expression of the melanoma cells. On the other hand, histamine was locally synthesized by the WM35 melanoma cells. CONCLUSION: We suggest that the growth arrest induced by IL-6 is in part mediated by its dual action on histamine: a shift toward H1 receptor predominance and an elevation of locally produced histamine with prevalent action on the inhibitory response triggered through the H1 receptor. These findings suggest a local cross-talk between histamine and IL-6 in the regulation of melanoma growth.

Headache: Treatment with Histamine

            (Leslie and Dunsworth 1947) Download

On the nature of histamine action

         (McDowall 1923) Download

Gastric stimulation for weight loss

         (Mizrahi, Ben Ya'acov et al. 2012) Download

The prevalence of obesity is growing to epidemic proportions, and there is clearly a need for minimally invasive therapies with few adverse effects that allow for sustained weight loss. Behavior and lifestyle therapy are safe treatments for obesity in the short term, but the durability of the weight loss is limited. Although promising obesity drugs are in development, the currently available drugs lack efficacy or have unacceptable side effects. Surgery leads to long-term weight loss, but it is associated with morbidity and mortality. Gastric electrical stimulation (GES) has received increasing attention as a potential tool for treating obesity and gastrointestinal dysmotility disorders. GES is a promising, minimally invasive, safe, and effective method for treating obesity. External gastric pacing is aimed at alteration of the motility of the gastrointestinal tract in a way that will alter absorption due to alteration of transit time. In addition, data from animal models and preliminary data from human trials suggest a role for the gut-brain axis in the mechanism of GES. This may involve alteration of secretion of hormones associated with hunger or satiety. Patient selection for gastric stimulation therapy seems to be an important determinant of the treatment's outcome. Here, we review the current status, potential mechanisms of action, and possible future applications of gastric stimulation for obesity.

Central histaminergic system and cognition

         (Passani, Bacciottini et al. 2000) Download

The neurotransmitter histamine is contained within neurons clustered in the tuberomammillary nuclei of the hypothalamus. These cells give rise to widespread projections extending through the basal forebrain to the cerebral cortex, as well as to the thalamus and pontomesencephalic tegmentum. These morphological features suggest that the histaminergic system acts as a regulatory center for whole-brain activity. Indeed, this amine is involved in the regulation of numerous physiological functions and behaviors, including learning and memory, as indicated by extensive research reviewed in this paper. Histamine effects on cognition might be explained by the modulation of the cholinergic system. However, interactions of histamine with any transmitter system, and/or a putative intrinsic procognitive role cannot be excluded. Furthermore, although experimental evidence indicates that attention-deficit hyperactivity disorder symptoms arise from impaired dopaminergic and noradrenergic transmission, recent research suggests that histamine is also involved. The possible relevance of histamine in disorders such as age-related memory deficits, Alzheimer's disease and attention-deficit hyperactivity disorder is worth of consideration, and awaits validation with clinical trials that will prove the beneficial effects of histaminergic drugs in the treatment of these diseases.

Plasma chromogranin A in patients with autoimmune chronic atrophic gastritis, enterochromaffin-like cell lesions and gastric carcinoids

            (Peracchi, Gebbia et al. 2005) Download

OBJECTIVE: In atrophic body gastritis (ABG) chronic hypergastrinaemia stimulates enterochromaffin-like (ECL) cell proliferation with development of cell hyperplasia, dysplasia and possibly type-1 gastric carcinoids. As circulating chromogranin A (CgA) levels are a marker of neuroendocrine tumours, we evaluated the clinical usefulness of CgA assay in ABG patients to detect those with carcinoids. DESIGN AND METHODS: Plasma CgA levels were measured using a commercial ELISA in 45 healthy volunteers, nine patients with type-1 gastric carcinoids and 43 consecutive ABG patients (21 without and 22 with ECL cell hyperplasia/dysplasia). RESULTS: CgA levels were significantly higher in ABG patients with and without gastric carcinoids than in healthy subjects (P < 0.001). The highest values occurred in patients with carcinoids (median (interquartile range): 58.1 (44.5-65.3) U/l) and with ECL cell hyperplasia/dysplasia (35.5 (31.8-48.65) U/l) but there were no significant differences in CgA among the various subgroups of ABG patients classified according to ECL cell status. Nevertheless, in ABG patients without carcinoids CgA values correlated with the presence and severity of ECL cell lesions (r(s) = 0.428, P < 0.01). The sensitivity and specificity of the CgA assay in identifying patients with carcinoids were 100 and 23% respectively. CONCLUSIONS: CgA plasma levels reflect the histological degree of ECL cell lesions in patients with ABG but the assay specificity is too low to detect among these patients those with gastric carcinoids.

New developments in the use of histamine and histamine receptors

         (Smuda and Bryce 2011) Download

Histamine and the histamine receptors are important regulators of a plethora of biological processes, including immediate hypersensitivity reactions and acid secretion in the stomach. In these roles, antihistamines have found widespread therapeutic applications, while the last receptor to be discovered, the H4 histamine receptor, has become a major target of novel therapeutics. Recent studies involving human genetic variance and the development of mice lacking specific receptors or the ability to generate histamine have shown roles for the histamine pathway that extend well beyond the established roles. These include identification of previously unappreciated mechanisms through which histamine regulates inflammation in allergy, as well as roles in autoimmunity, infection, and pain. As a result, antihistamines may have wider applications in the future than previously predicted.

Is the histaminergic neuron system a regulatory center for whole-brain activity?

         (Wada, Inagaki et al. 1991) Download

Recent immunocytochemical studies have demonstrated the existence of histaminergic neurons in the brain, which are concentrated in the tuberomammillary nucleus of the posterior hypothalamus, and which project efferent fibers to almost all parts of the brain. Three subtypes of histamine receptors are widely distributed in the brain, not only on neurons but also on astrocytes and blood vessels. Consistent with its wide-ranging output, the histaminergic neuron system regulates various activities of the brain, such as the arousal state, brain energy metabolism, locomotor activity, neuroendocrine, autonomic and vestibular functions, feeding, drinking, sexual behavior, and analgesia--this regulation is possibly achieved by the histaminergic system as a whole.

Histamine inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes

            (Wake, Takahashi et al. 2009) Download

Advanced glycation end products (AGEs) are modifications of proteins/lipids that become nonenzymatically glycated after contact with aldose sugars. Among various subtypes of AGEs, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) are suggested to play roles in inflammation in diabetic patients. Because the engagement of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, and CD40 on monocytes with their ligands on T cells plays roles in cytokine production, we examined the effects of AGE-2 and AGE-3 on the expression of adhesion molecules and cytokine production in human peripheral blood mononuclear cells (PBMC) and their modulation by histamine in the present study. AGE-2 and AGE-3 induced the expressions of ICAM-1, B7.1, B7.2, and CD40 on monocytes and the production of interferon-gamma in PBMC. Histamine concentration-dependently inhibited the action of AGE-2 and AGE-3. The effects of histamine were antagonized by an H2 receptor antagonist, famotidine, and mimicked by H2/H4 receptor agonists dimaprit and 4-methylhistamine. Histamine induced cAMP production in the presence and absence of AGE-2 and AGE-3. The effects of histamine were reversed by a protein kinase A (PKA) inhibitor, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89), and mimicked by a dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicated that histamine inhibited the AGE-2- and AGE-3-induced adhesion molecule expression and cytokine production via H2 receptors and the cAMP/PKA pathway.

Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells

            (Yang, Ai et al. 2011) Download

Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells, but its function in these cells is poorly understood. Here we show that Hdc-knockout mice show a high rate of colon and skin carcinogenesis. Using Hdc-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the Hdc promoter, we show that Hdc is expressed primarily in CD11b(+)Ly6G(+) immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wild-type recipients results in increased CD11b(+)Ly6G(+) cell mobilization and reproduces the cancer susceptibility phenotype of Hdc-knockout mice. In addition, Hdc-deficient IMCs promote the growth of tumor allografts, whereas mouse CT26 colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibit myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of tumor allografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation and CD11b(+)Ly6G(+) IMCs in early cancer development.

Histamine inhibits adhesion molecule expression in human monocytes, induced by advanced glycation end products, during the mixed lymphocyte reaction

            (Zhang, Takahashi et al. 2010) Download

BACKGROUND AND PURPOSE: Post-transplant diabetes mellitus is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor on monocytes/macrophages plays important roles in the genesis of diabetic complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T-cells, reducing allograft survival. Out of four distinct AGE subtypes (AGE-2, AGE-3, AGE-4 and AGE-5), only AGE-2 and AGE-3 induced expression of intercellular adhesion molecules (ICAMs), output of cytokines and proliferation of lymphocytes, during the mixed lymphocyte reaction (MLR). Here we have assessed the role of histamine in the actions of AGEs during the MLR. EXPERIMENTAL APPROACH: Human peripheral blood cells were used in these experiments. Flow cytometry was used to examine the expression of the ICAM-1, B7.1, B7.2 and CD40. Production of the cytokine interferon-gamma, and levels of cAMP were determined by elisa. Lymphocyte proliferation was determined by [(3)H]-thymidine uptake. KEY RESULTS: Histamine concentration dependently inhibited the action of AGE-2 and AGE-3. The actions of histamine were antagonized by an H(2)-receptor antagonist, famotidine, and mimicked by H(2)/H(4)-receptor agonists, dimaprit and 4-methylhistamine. The effects of histamine were reversed by a protein kinase A (PKA) inhibitor, H89, and mimicked by dibutyryl cAMP and an adenylate cyclase activator, forskolin. CONCLUSIONS AND IMPLICATIONS: Histamine down-regulated AGE-2- and AGE-3-induced expression of adhesion molecules, cytokine production and lymphocyte proliferation via histamine H(2) receptors and the cAMP/PKA pathway.


Akdis, C. A. and K. Blaser (2003). "Histamine in the immune regulation of allergic inflammation." J Allergy Clin Immunol 112(1): 15-22.

Burn, J. H. and H. H. Dale (1926). "The vaso-dilator action of histamine, and its physiological significance." J Physiol 61(2): 185-214.

Carlos, D., C. Fremond, et al. (2009). "Histamine plays an essential regulatory role in lung inflammation and protective immunity in the acute phase of Mycobacterium tuberculosis infection." Infect Immun 77(12): 5359-68.

Cui, G. and H. L. Waldum (2007). "Physiological and clinical significance of enterochromaffin-like cell activation in the regulation of gastric acid secretion." World J Gastroenterol 13(4): 493-6.

Elenkov, I. J., E. Webster, et al. (1998). "Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors." J Immunol 161(5): 2586-93.

Ferreira, R., T. Santos, et al. (2012). "Histamine modulates microglia function." J Neuroinflammation 9(1): 90.

Fossmark, R., G. Qvigstad, et al. (2008). "Gastric cancer: animal studies on the risk of hypoacidity and hypergastrinemia." World J Gastroenterol 14(11): 1646-51.

Grant, J. A., R. Alam, et al. (1991). "Histamine-releasing factors and inhibitors: historical perspectives and possible implications in human illness." J Allergy Clin Immunol 88(5): 683-93.

Kitano, M., M. Bernsand, et al. (2005). "Ischemia of rat stomach mobilizes ECL cell histamine." Am J Physiol Gastrointest Liver Physiol 288(5): G1084-90.

Lacour, M. and O. Sterkers (2001). "Histamine and betahistine in the treatment of vertigo: elucidation of mechanisms of action." CNS Drugs 15(11): 853-70.

Lambrecht, N. W., I. Yakubov, et al. (2007). "Fasting-induced changes in ECL cell gene expression." Physiol Genomics 31(2): 183-92.

Lazar-Molnar, E., H. Hegyesi, et al. (2002). "Inhibition of human primary melanoma cell proliferation by histamine is enhanced by interleukin-6." Eur J Clin Invest 32(10): 743-9.

Leslie, W. and F. A. Dunsworth (1947). "Headache: Treatment with Histamine." Can Med Assoc J 56(5): 509-12.

McDowall, R. J. (1923). "On the nature of histamine action." J Physiol 57(3-4): 146-52.

Mizrahi, M., A. Ben Ya'acov, et al. (2012). "Gastric stimulation for weight loss." World J Gastroenterol 18(19): 2309-19.

Passani, M. B., L. Bacciottini, et al. (2000). "Central histaminergic system and cognition." Neurosci Biobehav Rev 24(1): 107-13.

Peracchi, M., C. Gebbia, et al. (2005). "Plasma chromogranin A in patients with autoimmune chronic atrophic gastritis, enterochromaffin-like cell lesions and gastric carcinoids." Eur J Endocrinol 152(3): 443-8.

Smuda, C. and P. J. Bryce (2011). "New developments in the use of histamine and histamine receptors." Curr Allergy Asthma Rep 11(2): 94-100.

Wada, H., N. Inagaki, et al. (1991). "Is the histaminergic neuron system a regulatory center for whole-brain activity?" Trends Neurosci 14(9): 415-8.

Wake, H., H. K. Takahashi, et al. (2009). "Histamine inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes." J Pharmacol Exp Ther 330(3): 826-33.

Yang, X. D., W. Ai, et al. (2011). "Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells." Nat Med 17(1): 87-95.

Zhang, J., H. K. Takahashi, et al. (2010). "Histamine inhibits adhesion molecule expression in human monocytes, induced by advanced glycation end products, during the mixed lymphocyte reaction." Br J Pharmacol 160(6): 1378-86.