Histamine–cytokine connection in immunity and hematopoiesis

Cytokine & Growth Factor Reviews 15 (2004) 393–410 www.elsevier.com/locate/cytogfr

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Histamine–cytokine connection in immunity and hematopoiesis Michel Dy*, Elke Schneider1 CNRS UMR 8147, Paris V University, Hoˆpital Necker, 161 rue de Se`vres, 75743 Paris Cedex 15, France

Abstract A number of recent studies have led to a reappraisal of the functional capacities of histamine in immunity and hematopoiesis. This change of perspective was provided by the following findings: (1) the evidence for multiple cellular sources of histamine, differing from mature basophils and mast cells by their ability to newly synthesize and liberate the mediator without prior storage, (2) the discovery of a novel histamine receptor (H4R), preferentially expressed on hematopoietic and immunocompetent cells, (3) the potential intracellular activity of histamine through cytochrome P450 and (4) the demonstration of a histamine–cytokine cross-talk. Indeed, cytokines not only modulate the degranulation process of histamine but also control its neosynthesis by the histamine-forming enzyme, histidine decarboxylase (HDC), at transcriptional and post-transcriptional levels. In turn, histamine intervenes in the intricate cytokine network, regulating cytokine production by immune cells through distinct receptors signaling distinct biological effects. This type of regulation is particularly relevant in the context of TH1/TH2 differentiation, autoimmunity and tumor immunotherapy. # 2004 Elsevier Ltd. All rights reserved. Keywords: Histamine; Cytokines; Histidine decarboxylase; Immune responses; Hematopoiesis

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Histamine binding sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Classical histamine receptors . . . . . . . . . . . . . . . . . . . . 2.1.1. H1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. H2 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. H3 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. H4 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Non-classical histamine-binding sites . . . . . . . . . . . . . . 2.2.1. Cytochrome P450 . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Histamine transporters . . . . . . . . . . . . . . . . . . . . 2.2.3. Histamine-binding proteins . . . . . . . . . . . . . . . . . 3. Histamine synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Regulation of histamine synthesis . . . . . . . . . . . . . . . . . 3.2. HDC-deficient mice. . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Cellular sources of histamine . . . . . . . . . . . . . . . . . . . . 3.4. Histamine catabolism . . . . . . . . . . . . . . . . . . . . . . . . . 4. Histamine–cytokine connection . . . . . . . . . . . . . . . . . . . . . . 4.1. Histamine–cytokine connection during immune response . 4.1.1. Effect of histamine on immune cells . . . . . . . . . . 4.1.2. Effect of cytokines on histamine production . . . . .

* Corresponding author. Tel.: +33 1 44 49 53 93; fax: +33 1 44 49 06 76. E-mail address: [email protected] (M. Dy), [email protected] (E. Schneider). 1 Tel.: +33 1 44 49 53 94; fax: +33 1 44 49 06 76. 1359-6101/$ – see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2004.06.003

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4.2. Histamine–cytokine connection during autoimmunity . . . . 4.3. Histamine–cytokine connection during hematopoiesis . . . . 4.4. Histamine–cytokine connection during anti-tumor response 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Histamine was first discovered in 1910 by Sir Henry Dale [1], owing to its ability to constrict guinea pig ileum and its potent vasodepressor action, but it was only 17 years later that its presence in normal tissues was demonstrated [2]. At present, it is one of the monoamines (2-(imidazol-4-yl) ethylamine) with the broadest spectrum of activities in various physiological and pathological situations. Thus, it has been shown to be involved in aminergic neurotransmission and numerous brain functions (sleep/wakefulness, emotion, learning, memory, locomotor activity, nociception, food intake and aggressive behavior), secretion of pituitary hormones, regulation of gastrointestinal and circulatory functions, as well as inflammatory reactions and modulation of the immune response. Histaminergic neurons are located in the tuberomamillary nucleus of the posterior hypothalamus and project their axons into several brain regions, including the hypothalamus, thalamus, cerebral cortex, amygdale and septum. Histamine is produced by enterochromaffin-like cells (ECL) in the stomach and plays a role in gastric acid secretion. In the hematopoietic system, only mast cells and basophils can store the amine in specific granules, where it is closely associated with anionic proteoglycans and chondroitin-4-sulfate. In this form, it can be released in large amounts during degranulation in response to various immunological or non-immunological stimuli. More recently, other cellular sources of histamine have been discovered. In these occurrences, the cells express high levels of histidine decarboxylase (HDC), the activity of which results in the synthesis of histamine, which is immediately released, without prior storage. This so-called ‘‘neosynthesized histamine’’, has been demonstrated in many cells, including hematopoietic progenitors, macrophages, platelets, dendritic cells and T cells, and its production is modulated by cytokines. The numerous studies dealing with the effect of histamine during the immune response have given rise to several apparently conflicting data. These discrepancies might eventually be explained by the differential expression of histamine receptors (H1, H2, H3 or H4) that is easily modulated by the extracellular environment and may therefore vary with the experimental setup. All these receptors are heptahelical, G-protein-coupled (GPCR) and are expressed either ubiquitously (H1 and H2) or restricted to specialized cell populations (H3 in the brain and H4 in the hematopoietic system). In addition to these classical histamine receptors, intracellular binding sites of histamine have been identified on cytochrome P450 (CYP450). Even though the biological

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significance of this interaction is not clear yet, at least in immune cells, it is certainly an interesting issue for further investigations. Together with the recent discovery of the H4 receptor, these intracellular binding sites have to be taken into account for a better understanding of the role histamine plays in immunology. It is generally acknowledged that histamine can entertain a complex relationship with cytokines that influence the outcome of the immune response. Indeed, on the one hand, its synthesis in various hematopoietic populations is subject to regulation by cytokines like IL-3, GM-CSF, IL-1, and TNFa. On the other hand, histamine itself modulates the production of cytokines by T cells, dendritic cells, and macrophages. The aim of this review is to briefly summarize some general notions on histamine receptors and synthesis before focussing on some recent evidence supporting the existence of a histamine–cytokine connection in hematopoiesis and immunology.

2. Histamine binding sites 2.1. Classical histamine receptors 2.1.1. H1 receptor The human H1 receptor contains 486, 488 or 487 amino acids in rat, mouse and human respectively. It shares the typical features of GPCR, namely: seven transmembrane domains of 20–25 amino-acids predicted to form an a-helice that spans the plasma membrane and an extracellular NH2 terminal domain with glycosylation site. It is encoded by a single exon gene located on the distal short arm of chromosome 3p25 in humans and chromosome 6 in mice. Histamine binds to aspartate residues in the transmembrane domain 3 of the receptor and to asparagine + lysine residues within the transmembrane domain 5. H1 receptors are involved in the pathological process of allergy such as allergenic rhinitis, conjunctivitis, atopic dermatitis, urticaria, asthma and anaphylaxis. In the lung, it mediates bronchoconstriction and increased vascular permeability. The H1R is expressed in numerous cell types, including airway and vascular smooth muscle cells, hepatocytes, chondrocytes, nerve cells, endothelial cells, neutrophils, monocytes, dendritic cells, as well as T and B lymphocytes, in which it mediates the various biological manifestations of allergic responses [3–5]. H1R is a Gaq/11-coupled protein with a very large third intracellular loop and a relatively short C-terminal tail (Fig. 1). The main signal induced by ligand binding is the activation of phospholipase C-generating inositol 1,4,5-triphosphate (Ins (1,4,5) P3) and 1,2-diacylglycerol

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Fig. 1. The various classical and non-classical histamine binding sites and their main signal transduction pathways (DAO: diamine oxydase; HMT: histamine methyl transferase; OCT: organic cation transporter; HDC: histidine decarboxylase; CYP 450: cytochrome P450; HETE: 20-hydroxyeicosatrienoic acid; EET: eipoxyeicosatrienoic acids; VMAT: vesicular monoamine transporter; AC: adenylate cyclase; PKC: protein kinase C; PKA: protein kinase A; PLC: phospholipase C; H1+ or H2+: stimulation through H1 or H2 receptor; H3, H4: inhibition through H3 and H4 receptors).

leading to increased cytosolic Ca2+ [4]. This rise in intracellular calcium levels seems to account for the various pharmacological activities promoted by the receptor, such as nitric oxide production, vasodilatation, liberation of arachidonic acid from phospholipids and increased cyclic AMP. H1R also activates NF kB through Gaq11 and Gbg upon agonist binding, while constitutive activation of NF kB occurs through Gbg only [6]. Studies on the organization, genomic structure and promoter function of the human H1 receptor revealed a 5.8 kb intron in the 50 flanking region of this gene, various binding sites for several transcription factors and the absence of TATA and CAAT sequences at the appropriate locations [7]. The functional characterization of this receptor has benefited from the use of many potent and selective antagonists [3,8]. Indeed, H1R antagonists are among the oldest therapeutic tools of modern medicine. Because of their sedative side effects most of the anti-allergic drugs that were developed initially have been abandoned since. Indeed, as shown by the disturbance of circadian rhythms and locomotor activities as well as the impairment of the exploratory behavior in H1R-deficient mice, some effects of histamine in the brain are mediated through this receptor. This is why so-called ‘‘non-sedating’’ H1 antagonists that cannot cross the blood–brain barrier (such as cetirizine and loratidine) have been designed. In contrast to antagonists, H1R agonists are not readily available, because they do not present the same clinical prospects and would enhance rather than

prevent the onset of allergic pathologies. Nevertheless, the recently developed histaprodifens are very potent H1R agonists since they are more efficient than histamine in activating H1R [9] (Table 1). Recently, constitutive activity of the human wild-type H1R has been demonstrated, leading to the reclassification of some antagonists as inverse agonists. By definition, these molecules have a higher affinity for the inactive conformation of the receptor, which they stabilize. This is actually the case for the drugs most widely used to relieve the symptoms of allergy [10]. However, the exact physiological relevance of this constitutive activity remains to be elucidated. Some anti-inflammatory effects of H1 receptor antagonists at high doses could be non-specific [11]. This applies to release of histamine and other inflammatory mediators, like leukotriene and platelet activating factor, from basophils in response to certain H1R antagonists. The exact mechanism through which this effect occurs remains unclear and its clinical relevance is still uncertain. 2.1.2. H2 receptor The H2R belongs also to the GPCR family. Its intronless gene encodes a protein of 358 or 359 amino acids in rat or mouse and human, respectively. The human H2R is located on chromosome 5. Similarly to what has been described for the H1R, histamine binds to transmembrane domains 3 (aspartate) and 5 (threonine and aspartate). The short third intra-cellular loop and the relatively long C-terminal tail

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Table 1 Human histamine receptor characteristics Amino- Chromosomal Gene structure Antagonista acids localization H1 487

3p25

Intronless

H2 359

5

Intronless

H3 445

20

Three introns

H4 390

18q11.2

Two introns

a

Mepyramine, chlorpheniramine, cetirizine, astemizole, clemastine, terfenadine, loratidine, tripolidine Zolantidine, cimetidine, ranitidine, tiotidine, famotidine

Agonist

Expression

G protein

Histaprodifens

Ubiquitous (nerve cells, airway Gq and vascular smooth muscles, chondrocytes, endothelial cells, hepatocytes, T and B lymphocytes, DC, monocytes, eosinophils, neutrophils) Gs Dimaprit, amthamine, Ubiquitous (nerve cells, airway and impromidine, vascular smooth muscles, chondrocytes, amthamine endothelial cells, hepatocytes, T and B lymphocytes, DC, monocytes, eosinophils, neutrophils) Thioperamide, clobenpropit, Imetit, (R)-a-Methyl CNS, histaminergic neurons, low Gi/o carboperamide, iodoproxyfan, histamine, immepip expression in peripheral tissues ciproxyfan Thioperamide, JNJ 77771202 Clobenpropit, imetit, Mast cells, basophils, eosinophils, Gi/o clozapine DC, T cells, medullary hematopoietic precursors

Including inverse agonist.

constitute a remarkable feature of this sub-type [12]. The rat N-terminal extracellular tail contains N-linked glycosylation sites [12]. H2R is expressed in various cell types, similarly to H1R. It should be noted that H2R is mostly involved in suppressive activities of histamine, while positive effects are mediated through H1R. Initially thought to regulate a limited number of activities such as heart contraction and gastric acid secretion, it is now quite clear that various regulatory functions of histamine during cell proliferation, differentiation and immune response are exerted through H2R activation. H2R antagonists (even those penetrating the brain, such as zolantidine) do not affect the central nervous system. These compounds have proved to be very active in the treatment of stomach and duodenal ulcers, strongly suggesting that the clinical efficacy relates to the antagonistic effect of these drugs on stomach acid secretion. H2R is coupled both to adenylate cyclase and phosphoinositide second messenger systems by separate GTP-dependent mechanisms (Fig. 1). Receptor binding also induces activation of c-Fos, c-Jun, protein kinase C and p70S6kinase. However, H2R-dependent effects of histamine are predominantly mediated by cyclic adenosine monophosphate (cAMP). 2.1.3. H3 receptor The human H3R is also G protein-coupled and has been cloned more recently [13]. Its gene consists of four exons spanning 5.5 kb on chromosome 20. It has initially been identified in both central and peripheral nervous system as a presynaptic receptor controlling the release of histamine and other neurotransmitters (dopamine, serotonine, noradrenalin, GABA and acetylcholine). H3R signal transduction involves Gi/o proteins (inhibited by Bordetella pertussis toxin), the activation of which leads to inhibition of cAMP formation, accumulation of Ca2+ and activation of mitogen-

activated protein kinase pathway (MAPK). Many in-depth studies have allowed the development of several selective agonists and antagonists (Table 1). H3R are mainly involved in brain functions, even the peripheral effect of histamine on mast cells through H3 receptors, which involves the nervous system and might be related to a local neuron-mast cell interaction [14]. Apparent H3R heterogeneity in binding and functional studies has been described, suggesting the existence of more than one H3R subtype. This assumption has been confirmed by the demonstration of several H3R variants generated from the complex H3R gene by alternative splicing. In the rat, three functional isoforms have been found. They vary in the length of the third intracellular loop, their distinct central nervous system localization and differential coupling to adenylate cyclase and MAPK signaling pathways. Similar results were obtained in humans [15–17]. H3R display constitutive activity, which means that part of the receptor population spontaneously undergoes allosteric transition leading to a conformation, to which G protein can bind [18,19]. H3R-deficient mice manifest an obese phenotype, characterized by increased body weight, food intake, adiposity and reduced energy expenditure. They express insulin and leptin resistance as well as a diminution of the energy homeostasis-associated genes UCP1 and UCP3 [20]. 2.1.4. H4 receptor The human H4R gene, mapped to chromosome 18q11.2, encodes a 390 amino acid, seven transmembrane G-protein– coupled receptor. It shares with the H3R 37–43% homology (58% in transmembrane regions) and a similar genomic structure. The H4R gene spans more than 21 kbp and contains three exons, separated by two large introns (>7 kb). Analysis of the 50 flanking region did not reveal the canonical TATA or CAAT-boxes. The promoter region contains

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several putative regulatory elements involved in proinflammatory cytokine signaling pathways. H4 receptors are coupled to Gi/o, initiating various transduction pathways such as inhibition of forskolin-induced cAMP formation, increased calcium influx and MAPK activation. In accordance with the homology between the two receptors, various H3R agonists and antagonists are recognized by the H4R, albeit with different affinities. For example, the H3R agonist R-a-methyl histamine acts on H4R, but is several hundred times less potent. Thioperamide, the classical H3 antagonist behaves like a H4 antagonist, though with a much lower affinity. Clobenpropit, another H3 receptor antagonist, exerts agonistic activity on H4R [21–27]. Although histamine binding to H4R is very similar to that reported for the other histamine receptors (importance of the Asp 94 residue in transmembrane region(TM) 3 and the Glu 182 residue in the TM5) some differences exist, and could be exploited to design specific tools. Mouse, rat and guinea pig H4 receptors have been cloned and characterized [28]. They were only 68, 69, and 65% homologous, respectively, to their human counterpart. These studies have revealed substantial pharmacological variations between species, with higher affinity of histamine for human and guinea pig receptors than for their rat and mouse equivalents. Whatever the species, tissular H4R distribution seems to be identical. H4R transcripts are mainly expressed in medullary and peripheral hematopoietic cells, including eosinophils, basophils, mast cells, T lymphocytes and dendritic cells. However, low positive signals have also been detected in brain, liver and lung. The relatively restricted expression of the H4R suggests a role in inflammation, hematopoiesis and immunity. Up to now, very little is known about the biological functions of H4R. There are only few reports in the literature, providing evidence for chemotactic activity in mast cells and eosinophils or control of IL-16 production by CD8+ lymphocytes [29–32]. Obviously, a better functional characterization of this receptor will benefit from the exploitation of new, specific tools, such as the recently developed potent, selective non-imidazol H4 receptor antagonist and H4R-deficient mice [31,33]. 2.2. Non-classical histamine-binding sites 2.2.1. Cytochrome P450 The human cytochrome P450 (CYP450) superfamily comprises 57 genes encoding heme-containing enzymes. They are not only involved in the metabolism of a large number of foreign substances, but play a crucial role in diverse physiological processes, such as generation, transformation or inactivation of endogenous ligands (steroids and lipids) that participate in cell regulation [34,35]. For example, it is generally acknowledged that CYP450 constitute the third pathway of arachidonic acid metabolism, leading to the production of epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatrienoic acid (20-HETE), products that are involved in inflammation and control of

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cellular proliferation [36–38]. Molecules of the CYP450 family are found in the liver as well as in extrahepatic tissues, such as adrenals, and peripheral blood leukocytes, where they can be induced by various stimuli [39,40]. Their inhibition may lead to clinically significant drug-drug interactions and metabolic alterations. Histamine binding to CYP450 has been demonstrated by L. Brandes, who proposed a second messenger role for intracellular histamine through this binding site. This assumption is essentially based on the finding that N,Ndiethyl-2-(4-(phenylmethyl)phenoxy) ethanamine (DPPE), an arylalkylamine analogue of tamoxifen inhibits the binding of histamine to CYP450 [41,42]. Indeed, by occupying the catalytic sites of CYP450 enzymes, DPPE allosterically modified histamine binding to the heme moiety of these molecules and inhibited platelet aggregation, as well as lymphocyte and hematopoietic progenitor proliferation [43–45]. As a matter of fact, the effect of DPPE on histamine binding is more complicated and depends on the nature of the P450 enzymes. Thus, it inhibits the action of histamine on CYP2D6 and CYP1A1, enhances its effect on CYP3A4 and does not affect CYP2B6 [46]. Based on the cytoprotective/chemopotentiating effects of DPPE, clinical trials associating DPPE and chemotherapeutic treatment have been performed in patients suffering from hormone-refractory prostate and metastatic breast cancer. Results were sufficiently encouraging to pursue additional phase III studies [47–49]. The heme moiety of CYP450 binds also various histamine antagonists [50–53], particularly H3 receptor antagonists, such as thioperamide, clobenproprit and ciproxyfan [54,55]. This property could explain some effects of these antagonists when used at high doses. In accordance with the demonstration that histamine interacts with CYP450, it has recently been demonstrated that CYP2E1 and CYP3A are upregulated in histidine decarboxylase-deficient mice [56]. 2.2.2. Histamine transporters Histamine, which is synthesized in the cytosol, requires a means of transport into secretory vesicules in which it is sequestered. Vesicular monoamine transporters (VMATs) are proteins that accomplish this task for various neurotransmitters [57]. Among the two subtypes of monoamine transporters, VMAT1 and VMAT2, that have been cloned and characterized, only the latter can transport histamine. VMAT2 has been cloned from rat and human brain, bovine adrenal medulla and a basophilic leukemia cell line. Its expression is upregulated by various stimuli, more particularly when histamine biosynthesis is increased. Indeed, increased VMAT2 expression in IL-3-dependent cell lines, parallels increased histamine synthesis in response to calcium ionophore [58,59]. Enterochromaffin-like (ECL) cells are a neuro-endocrine subset present in the gastric epithelium that synthesize and release histamine, which is critical in the control of gastric

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acid secretion via H2R present on acid-secreting parietal cells. VMAT2 is responsible for the transport of histamine into secretory granules of ECL. Its gene expression can by modulated by cytokines, either negatively (IL-1 and TNFa) or positively (TGFa) [60]. Studies in VMAT2-deficient mice have established that histamine is no longer stored when the transporter, which is normally expressed in the granule membrane of mast cells is lacking. Indeed, the VMAT2-deficient granules do not release histamine upon stimulation, even though granulecell fusion does still occur [61]. Bone marrow-derived mast cells from HDC (histidine decarboxylase)-deficient mice are totally devoid of endogenous histamine, but can take up the mediator from histamine-supplemented medium and store it in secretory granules. In this case, two transporters are necessary: first, to insure the passage across the plasma membrane, second, to cross the vesicular membrane. The first transporter has not been identified yet and the second seems to be VMAT2. As a rule, transport of small molecules from the medium across the plasma membrane is an energy-consuming rather than a passive process since it does not occur at low temperature [62]. We have reported several years ago that normal bone marrow cells can bind and internalize histamine from the extracellular compartment by an active temperature-dependent mechanism. The cells endowed with this property and those, which synthesize histamine in response to IL-3, are identical and have been characterized as precursors of the basophil lineage [63]. H1 and H2 receptor antagonists did not affect histamine uptake by bone marrow cells, and although H3 receptor antagonists were quite effective at relatively low doses, H3 receptors were also not involved in this process [64]. Experiments with H3R- and H4R-deficient mice will provide the definite proof that histamine uptake by bone marrow cells does not result from internalization through either receptor. Taken together, these data suggest that professional histamine-producing cells of the mast cell and basophil lineage share the capacity to take up histamine from their microenvironment. The physiological relevance of this process is not clear, so far. However, these membrane transporters of histamine could explain why histamine is present in mast cells from HDCdeficient mice fed on a histamine-containing normal diet, while it is no longer detected when a histamine-free food is provided. Non-neuronal monoamine transporters, which actively remove monoamines from extracellular space, have been described: organic cation transporter 1 (OCT1), OCT2 and extraneuronal monoamine transporter (EMT, also called OCT3). OCT1 expression is restricted to liver, kidney and intestine, OCT2 expression has been demonstrated in brain and kidney, while EMT has a broad tissue distribution. As shown by Gru¨ ndemann et al., OCT1 cannot transport histamine, conversely to OCT2 and EMT for which it is a good substrate [65]. This is why EMT seems to be a good candidate for the role of histamine transporter in basophils

and mast cells, accounting for their capacity to take up the mediator from the environment. 2.2.3. Histamine-binding proteins Studies on blood-sucking arthropods have provided evidence for several new histamine-binding proteins. Indeed, the saliva of insects like Rhodnius prolixus contains a family of proteins called nitrophorins. During blood feeding, these molecules trap histamine. Similarly, Rhipicephalus, a species of ixodid ticks, which remain attached to their hosts for extended periods of time, produce several histamine-binding proteins. In this way they protect themselves against the amine, which participates in the process of their rejection. These molecules are lipocalins, they are highly specific for histamine, and could offer new strategies for controlling histamine-based diseases [66,67].

3. Histamine synthesis 3.1. Regulation of histamine synthesis Histamine is synthesized by catalytic decarboxylation of histidine by L-histidine decarboxylase (HDC) (EC 4.1.1.22), which requires binding of the cofactor pyridoxal-50 -phosphate to a putative binding site (TFNPSKW) on the protein. Histamine cannot be synthesized by another enzymatic pathway. HDC cDNAs have been isolated from fetal rat liver, human basophil leukemia cells, mouse mastocytoma and erythroleukemia cells. Structural studies have revealed that both mouse and human genes are composed of 12 exons, spanning approximately 24 kb. The mouse gene produces a single transcript of 2.4 kb, whereas two splice variants of 3.4 kb and 2.4 kb exist in humans, the latter encoding the functional HDC [68]. The HDC gene is located on chromosome 15 in humans and chromosome 2 in mice. Its expression is controlled by lineage-specific transcription factors, which interact with a promoter region comprising a GC box, four CACC boxes, four GATA consensus sequences and a c-Myb-binding motif [69]. In gastric cancer cells, HDC transcription is controlled by gastrin, PMA and oxidative stress, through a protein kinase C, a Ras-independent, Raf-dependent mechanism and MAP kinase/ERK pathways acting on three overlapping cisacting elements known as gastrin response elements (GASRE1, GAS-RE2 and GAS-RE3). They are located downstream of the transcriptional start site and bind at least three distinct nuclear factors [70–72]. Gastroduodenal ulcers are associated with helicobacter pylori infection that enhances HDC expression and consecutively increases gastric acid production. Transactivation of the HDC promoter during infection with helicobacter pylori results from a signaling cascade involving MEK-1-2/ERK 1-2, cAMP-dependent activation of Rap1 and B-Raf [73]. In addition, the transcription factors GATA-4 and GATA-6 are expressed in a gastric epithelial cell line, where they exert a negative

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control on HDC expression [74]. The regulation of the HDC gene in hematopoietic cells is largely unknown, apart from the observation that nuclear factor E2 (NF-E2) seems to be involved indirectly [75]. The preferential expression of HDC in mast cells and basophils appears to be a consequence of the state of CpG methylation in the promoter region [76]. Thus, chromosomal configuration and methylation of the HDC promoter are likely to account for its cell-specific expression. HDC gene expression is also subject to post-transcriptional control, as suggested by studies on the mast cell line HMC1 [77,78] and the pluripotent hematopoietic cell line UT7D1 [79]. Indeed, in this latter cell line, PMA induces a strong increase in HDC activity that is only slightly affected by actinomycin D and not paralleled by increased HDC mRNA expression. A similar effect is observed in cell lines with megakaryocyte/basophil differentiation potential, like HEL and CMK [79]. This effect is explained by a translational control of HDC expression, a mechanism that accounts also for the strong enhancement of HDC activity in ECL cells in response to gastrin [80]. In hematopoietic cells, our results support the involvement of two essential mechanisms of translational control: 1/a rapamycin-dependent pathway, linking phosphoinositide 3-kinase (PI3K), FRAP/mTOR and phosphorylation/dephosphorylation of repressor of translation 4E-binding proteins (4E-Bps) and 2/ERK- and p38-dependent control of 4E-BP expression through induction of Egr-1 [81]. Post-translational processing of HDC leads to the formation of multiple carboxytruncated isoforms. In mammals, the HDC gene is initially translated as a 73–74 kDa protein. Originally, it was assumed that enzymes purified from native sources corresponded to a dimer of two processed isoforms of 53 and 55 kDa. However, though histamine biosynthesis involves primarily the 55 kDa isoform, it is presently acknowledged that various other isoforms generated from the 74 kDa primary translation product can also be active [82]. It is noteworthy that another means of promptly enhancing HDC activity might consist in reducing mRNA degradation through amino and carboxyl-terminal PEST domains [83]. Negative feed back regulation of HDC activity is not yet completely understood, and might differ from one cell type to another. In AGS-B cells, it has been shown that overexpression of the HDC protein inhibited HDC promoter activity through downregulation of ERK signals [84]. However, this type of feed back mechanism was not observed in gastrin-stimulated ECL cells. In the stomach as well as in hematopoietic cells (personal data) negative feed back signals could be generated by high cytosolic histamine concentration [80]. 3.2. HDC-deficient mice Mice with undetectable tissue HDC levels were generated by targeted disruption of the HDC gene [85]. Surprisingly, histamine was still present at low levels in various tissues,

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but disappeared upon feeding on a histamine-free diet. This finding revealed a transport system for exogenous histamine in various cell types that could at least partially compensate for the lack of endogenous histamine synthesis [62]. Abrogation of histamine synthesis in the brain produces both positive and negative effects on memory, depending on the nature of the task that has to be performed [86]. It also causes changes in the cortical electroencephalogram and a sleepwake cycle that renders HDC/ mice unable to stay awake when high vigilance is required in response to behavioral challenge [87]. In agreement with the anorexic effect of histamine with decreased appetite and fat accumulation, aged HDC/ mice are characterized by visceral adiposity, increased volume of brown adipose tissue, impaired glucose tolerance, hyperinsulinemia and hyperleptidemia with a defective mobilization of energy stores [88]. The notion that histamine production is essential for gastric acid secretion induced by gastrin was also confirmed in these mice [89]. Furthermore, HDC deficiency results in increased bone mineral density, cortical bone thickness, higher rate of bone formation and a marked decrease in osteoclasts, which could explain why these mice are protected against bone loss occurring after ovariectomy [90]. With respect to allergic skin reactions, experiments with HDC/ mice have confirmed histamine as an important mediator, especially for plasma extravasation [62]. HDC/ mice have abnormal mast cells with reduced granular content [91,92], a feature that could, at least partially, account for the observed reduction of antigen-induced airway hyperresponsiveness, eosinophilia and allergen-specific IgE production in the experimental model of asthma [93,94]. These mice are less sensitive to experimental peritonitis induced by E. coli, suggesting that histamine causes a delay in the elimination of these bacteria by decreasing neutrophil recruitment [95,96]. Conversely to mast cell-deficient mice (W/Wv), HDC/ mutants display reduced angiogenesis with lower levels of VEGF in granulation tissue. It can therefore be assumed that histamine derived from cellular sources distinct from mast cells augments angiogenesis by inducing VEGF production via the H2R, cAMP, PKA pathway [97]. 3.3. Cellular sources of histamine There are several long-established sources of histamine, such as mast cells and basophils, gastric enterochromaffinlike cells and histaminergic neurons. Mast cells and basophils represent the most important pool of cells capable of storing and promptly liberating histamine upon stimulation. Mast cells reside in various tissues of the organism, conversely to basophils, which represent the mobile pool of the amine. Both cells derive from CD34+ hematopoietic stem cells. Mast cells leave the bone marrow as immature precursors and complete their differentiation in peripheral tissues. Conversely, basophils enter the circulation only when they have achieved full maturation in the bone marrow

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[98–100]. It is generally accepted that mast cells and basophils represent distinct cell lineages derived from different progenitors. However, the possibility of a common mast cell/ basophil progenitor is supported by the expression of a common antigen expressed by mature basophils and mast cells, as well as their precursors recognized by the antibody 97A6 [101] and the identification of cells with metachromatic granules sharing the features of both basophils (blood location, segmented nuclei and expression of Bsp1, a basophil specific antigen) and mast cells (c-kit, tryptase and chymase expression) in the peripheral blood of patients with asthma, allergy and allergic drug reactions [102]. Mast cells and basophils are regarded as key effector cells in IgEassociated immediate hypersensitivity reactions and allergic disorders. Although basophils have been described over a century ago, they remain enigmatic in terms of their physiological functions. However, recent data suggest that they may play an important role during helminth infections, and are more efficient than mast cells in producing IL-4 together with histamine, which both facilitate TH2 differentiation [103]. Mast cells and basophils share the expression of FceRI, a tetramer composed of one a, b and two g chains (abg2). Cross-linking of FceRI-bound IgE with antigen, initiates degranulation with subsequent release of stored mediators, like histamine, de novo synthesis of pro-inflammatory lipid mediators and production of cytokines and chemokines. In these conditions, the amount of histamine liberated into the microenvironment may reach millimolar levels. This process is enhanced by high concentrations of IgE, which upregulate membrane FceRI expression. In addition, recent data indicate that monomeric IgE can increase survival of mast cells without cross-linking, by rendering them resistant to apoptosis. This type of stimulation is efficient enough to induce cytokine production and increased HDC activity through a signaling pathway, distinct from the one activated upon antigen-stimulated FceRI cross-linking [104]. Several other hematopoietic cell lineages have been shown to synthesize histamine, though at 100–1000-fold lower levels than mast cells and basophils. The proof for this biological activity in hematopoietic populations devoid of mature or morphologically recognizable mast cells or basophils was provided by the assessment of HDC activity. In the absence of specific granules for storage, these cells display a high enzymatic activity and low intracellular levels of histamine, which is secreted immediately after synthesis. To mark the distinction from its stored form, the histamine thus generated has been called ‘‘neosynthesized’’ or ‘‘nascent’’. We have first demonstrated this neosynthesis during the immune response, showing that myeloid cells distinct from mature mast cells or basophils can produce high levels of histamine during mixed leukocyte culture or mitogenic stimulation [105,106]. Other investigators, who reported high HDC activity in non-mast cells after treatment with lipopolysaccharide (LPS) or staphylococcal enterotoxin A (SEA) [107–109] have confirmed this characteristic, which

seems to be shared by other cell types, such as platelets, monocytes/macrophages, dendritic cells, neutrophils and lymphocytes [43,110–114]. In accordance with this unexpected diversity of histamine-producing cells, various pluripotent hematopoietic cell lines, such as UT7, UT7D1, HEL, CMK and LAMA84 respond to PMA by increased histamine synthesis [79,115], in addition to the basophilic cell line KU812F or the mast cell line HMC1. This is also the case in murine non-mast cell, non-basophil IL-3-dependent cell lines like FDCP1, FDCP2, BAF/3 and Ea3 in response to calcium ionophore [59]. 3.4. Histamine catabolism It is noteworthy that, once released, histamine levels can be further controlled by the metabolizing enzymes diamine oxidase (DAO) and N-methyltransferase [116]. This degradation of histamine has to be considered during in vitro experiments currently performed with fetal calf serum, which contains variable levels of diamine oxidase, depending on the batch [117].

4. Histamine–cytokine connection Immune response and hematopoiesis are controlled by a complex network of cytokines and chemokines. Histamine, originally considered as a mediator of immediate hypersensitivity, might play a more complex role than expected by intervening in this cytokine network. Indeed, the cells involved in the regulation of immune responses and hematopoiesis express histamine receptors on their surface, and most of them can also produce the mediator. The interactions between these molecules are bidirectional since histamine modulates immune cell functions and cytokines control histamine synthesis and release as well as histamine receptor expression [118–121]. 4.1. Histamine–cytokine connection during immune response 4.1.1. Effect of histamine on immune cells Studies on H1 receptor-deficient mice have revealed that their lymphocytes proliferate less than their wild-type counterpart upon stimulation with anti-CD3 or specific antigen [122]. On the other hand, histamine enhances the proliferative response of mouse T and B lymphocytes, in a dosedependent manner. This activity is mediated through H1R, since it did not occur in H1R/ mice. However, T cell proliferation in response to cytokines is normal in these mutant mice, suggesting that H1R activation contributes primarily to antigen receptor-mediated signaling pathways that lead to cytokine production. The importance of cytokines like IL-12, IL-27 and IL-23 for TH1 and IL-4 for TH2 differentiation, and the role of

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these CD4 T cell subsets in the control of delayed type hypersensitivity or humoral allergic responses, respectively, are firmly established by now. It has been shown only three years ago that histamine can exert a differential effect on these subsets, which is explained by their distinct receptor expression, the H1 subtype being predominant in the TH1 population, whereas TH2 cells preferentially express H2R [123]. Histamine enhances TH1-type responses by triggering the H1 receptor, while both TH1 and TH2 cells are negatively regulated through H2R. In accordance with this observation, mutant mice lacking the H1R gene have less IFNg-producing T cells and produce more TH2 type cytokines (IL-4 and IL-13) and IgE than wild type controls. Conversely, in H2R-deficient mice the production of both TH1 and TH2 cytokines is upregulated. IL-3 is a well-known differentiation and growth factor for mast cells and basophils and a potent inducer of HDC in hematopoietic cells. It can also increase the expression of H1R on TH1 but not on TH2 cells. This activity might represent a negative feed back mechanism of the allergic response, because of the antiallergic role of IFNg produced by TH1 cells (Fig. 2). B cell proliferation in response to anti-IgM is increased in response to histamine and diminished in H1R-deficient mice, suggesting that H1R signaling can amplify B cell receptor stimulation. Concerning the antibody response to T celldependent antigen, two different results have been reported. Indeed, ovalbumin-specific IgE and IgG1 antibody production was increased in H1R-deficient mice, while IgE and IgG3 production was decreased in H2R-deficient mice. In the latter situation ovalbumin-specific IgE levels dropped,

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even though IL-4 and IL-13 production was enhanced, because of the high concentration of IFNg, which is inhibitory. This finding supports the idea that H1R and TH1 responses are prevailing over humoral responses [122,123]. Myeloid dendritic cells (DC) are professional antigenpresenting cells residing in peripheral non-lymphoid tissues in their immature form. At this stage of differentiation they are very efficient in capturing antigens, which trigger their migration to secondary lymphoid organs. While migrating, they undergo phenotypic and functional changes, termed DC maturation, and become potent antigen-presenting and cytokine-producing cells, ready to stimulate T cells. Because these cells are often located in the vicinity of various sources of histamine, such as connective tissue mast cells, their interactions with this mediator have been largely investigated. Human dendritic cells express high levels of H1 and H2 receptors, which are downregulated during maturation, and low, variable H3R levels [124]. We have recently established that they also express H4R mRNA (personal data). Even though DC cannot fully differentiate in response to histamine alone, they display more CD86 and increase their chemokine production [125]. In combination with differentiating stimuli like LPS, histamine exerts a potent polarizing effect towards TH2-promoting DC (DC2), characterized by reduced IL-12 and enhanced IL-10 production (Fig. 2). This effect is mainly mediated through H2 receptors, although H1 receptor activation might occasionally be involved [125–127]. Plasmacytoid DC (pDC) constitute another subset of professional antigen-presenting cells and a major source of IFNa. Similarly to what happens

Fig. 2. Histamine acts as a pro-TH2, anti-TH1 mediator during TH differentiation by modulating cytokine production by antigen-presenting cells (APC). Furthermore, it hampers TH2 activity of differentiated cells via H2 receptors which are preferentially expressed on TH2 cells. Histamine can also stimulate TH1 proliferation via H1 receptors, preferentially expressed on TH1 cells, thus providing an additional anti-TH2 signal via increased IFNg production (THp: T helper precursor).

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in myeloid DC, histamine modulates their cytokine production through H2 receptors. Indeed, the presence of histamine during stimulation of pDC by live flu virus or CpG oligodeoxynucleotides markedly decreases their IFNa and TNFa production [128]. This may explain why low levels of type I IFN are associated with viral infection in atopic children. It has also been reported that human myeloid DC derived from monocytes in response to GM-CSF + IL-4 express HDC during their differentiation process, which is impaired in the absence of endogenous histamine in HDC-deficient mice [111]. Finally, it seems that the interactions between histamine and dendritic cells are not necessarily the same in human and murine models [129,130]. In the latter, histamine has either no effect or influences the functional state of mature DC differentially, depending on the factors employed to induce maturation. In striking contrast with the expression of the functional H1 and H2 receptors on myeloid DC and dermal dendritic cells, Langerhans cells express neither H1 nor H2 receptors, mainly because of the negative effect of TGFb1 required for their differentiation [131]. Histamine can also promote decreased p40 and p70 IL-12 and increased IL-10 production through its H2 receptors in lipopolysaccharide (LPS)-stimulated whole blood cells or purified monocytes [132,133] (Fig. 2). These data are reminiscent of the work of Rocklin et al. who demonstrated several years ago a histamine-induced suppressor T cell factor derived from monocytes [134], which, in the light of the present data, could be identical with IL-10. Histamine can also inhibit LPS-induced TNFa production by monocytes via its H2 receptor [135]. This activity might be due to its capacity to downregulate CD14 membrane expression on monocytes without affecting TLR4 expression [136]. The modulation of CD14 occurs probably through post-transcriptional events since mRNA levels remained unchanged. It is although noteworthy that histamine diminishes IL-18induced IFNg, TNFa and IL-12 production by human PBMC. IL-18 exerts this effect through upregulation of ICAM on monocytes, and histamine prevents this enhancement through its H2 receptors, while it has no effect in the absence of IL-18 [137]. Among the reasons for the renewed interest in histamine research for immunologists the new H4 receptor discovered three years ago is certainly an important one, considering its preferential expression in bone marrow and immunocompetent cells, such as mast cells, basophils, eosinophils, T lymphocytes and dendritic cells. Low H4R expression has been detected in non-hematopoietic organs, but a possible contamination by blood cells cannot be excluded. Although this restricted expression of the H4R is consistent with its potential role during the immune response, it is quite intriguing that, up to now, very little has been reported on its functions. Among the data available, the involvement of H4 receptors in histamine-induced chemotaxis of eosinophils and mast cells has been clearly established. In addition, changes of eosinophil shape and increased expression of adhesion molecules like CD11b/CD18(Mac1) and

CD54(ICAM-1) appear to be mediated likewise through this receptor [29–31], which is also involved in leukotriene B4- and mast cell-dependent neutrophil recruitment induced by zymosan in vivo [138]. Lastly, histamine is recognized as a potent stimulus for IL-16 production by CD8+ T cells via H2 or H4 receptors [30], which are both expressed in this T cell subset. The finding that H4R expression can be modulated by IL-4 and IL-13 is suggestive of a possible implication in the regulation of immune responses, which will eventually receive further support when new functions of the H4R will be discovered. Vascular endothelial growth factor is a potent inducer of angiogenesis. In addition to hypoxia or PGE2, it has also been demonstrated that histamine induces VEGF production in granulation tissue via the H2 receptor-cyclic AMP-protein kinase A pathways [139]. Histamine can also interfere with cytokine signaling pathways. For example, by interacting with the H2 receptor on tumor cells it triggers a cAMP/PKA signaling pathway that inhibits IFNg-induced signal transducer and activator of transcription 1 (STAT1) and suppresses interferon induced protein IP-10 synthesis [140]. Even though most effects of histamine on cytokine production are certainly mediated through classical histamine receptors, several data obtained with H1 and H3 receptor antagonists at more than saturating concentrations (personal data) might be explained by other mechanisms and are of potential pharmacological interest. 4.1.2. Effect of cytokines on histamine production IL-3 induces differentiation of basophils as well as mast cells in synergy with SCF. In vivo treatment of rhesus monkeys with IL-3 leads to increased generation of histamine-releasing cells that could be atypical basophils, because they do not stain with basophilic dyes, such as toluidine and alcian blue [141]. Some side effects of IL-3 such as urticaria and edema could be due to these cells. IL-3 and GM-CSF are also enhancers of histamine release by normal human basophils, while SCF plays a similar role for mast cells [142,143]. Furthermore, it turned out that histamine releasing factor (HRF) can prime or induce histamine release from basophil/mast cells. This protein was initially described as an activity appearing in late phase response fluids from nasal or bronchoalveolar lavages that directly induced histamine release from basophils in responders (HRF responders). HRF is neither a cytokine nor a chemokine, but was found to be identical with transcriptionally controlled tumor protein (TCTP, also named p23). Nevertheless, it functions like a cytokine modulating histamine and cytokine production in various cell types [144]. The effect of cytokines is especially potent on neosynthesized histamine by cells differing from mature basophils or mast cells. The proof that several hematopoietic populations devoid of mature or morphologically recognizable mast cells or basophils can generate histamine was provided by the assessment of HDC activity [145,146]. We first demonstrated

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this process during mixed leukocyte cultures between allograft donors and recipients or in response to polyclonal T cell activation by Con A or anti-CD3 mAb. Later on, other groups reported increased HDC activity in myeloid cell populations stimulated with LPS or staphylococcal enterotoxin A (SEA). HDC activity is easily modulated both in vitro, in response to cytokines like IL-3, GM-CSF, IL-1, IL-18, IL-12, M-CSF and TNFa [145–150] and in vivo, during allograft rejection, infection, inflammation and stimulation with LPS [105,106,151,152]. Basophil precursors generate histamine upon exposure to IL-3, GM-CSF, calcium ionophore or phorbol 12-myristate 13-acetate (PMA) [59,153,154]. These features are reminiscent of those reported for a bone marrowderived ‘‘histamine-producing cell’’ without granules in murine skin, which responds to PMA by increased HDC activity [155]. IL-1, TNFa or LPS alone cannot induce histamine production by basophil precursors, but act in synergy with GM-CSF to enhance its effect. Their effect is explained by PGE2 and intracellular AMPc, which accumulate in response to these factors and enhance the increase in histamine synthesis induced by GM-CSF [156]. Bone marrow-derived cells of the macrophage lineage can also generate histamine upon exposure to LPS [157]. They do not respond to IL-3 and/or GM-CSF alone, conversely to cells from the basophil lineage. However, in synergy with LPS these growth factors can enhance histamine production. It has also been demonstrated that most IL-3-dependent murine hematopoietic progenitor cell lines synthesize histamine in response to calcium ionophore or PMA [59]. De novo synthesis of histamine has also been reported in rat inflammatory tissues during the late phase of the allergic reaction. It results from the effect of GM-CSF on cells, which are not related to the mast cell or basophil lineage. Using in situ hybridization, Shiraishi et al. demonstrated that the incidence of cells expressing HDC mRNA in these inflamed tissues correlated with that of neutrophils (around 90%). The identity with this granulocyte subset was consistent with the demonstration that peritoneal neutrophils respond to in vitro stimulation with PMA by increased histamine synthesis [113]. Other myeloid and lymphoid cell populations have been claimed to express HDC activity under certain circumstances, such as platelets, dendritic cells and T lymphocytes. The amounts of histamine produced differ widely from one cell type to another. For example, pure bone marrowderived macrophages exposed for 48 h to high doses of LPS generate on average 20 or 600 times less histamine than total bone marrow cells or enriched basophil precursors stimulated with IL-3, respectively. Thus, several cellular sources controlled by various cytokines may contribute to the quantity of histamine actually available in the microenvironment. Histamine synthesis in hematopoietic cells can also be subject to negative control, as exemplified by the effect of IFNg on bone marrow-derived macrophages and of pro-TH1 cytokines on the basophil lineage. In the latter case, a negative regulation of peripheral basophil precursors

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exposed to IL-12 plus IL-18 occurs through Fas-dependent apoptosis assessed by the following findings: (1) histamine synthesis by spleen cells recovered after in vitro or in vivo treatment with these cytokines was substantially reduced in wild type but not in Fas- or FasL-deficient mice; (2) stimulated splenocytes killed Fas-transfected L1210 cells; (3) the inhibitory effect on histamine synthesis was diminished in the presence of the large spectrum caspase inhibitor zVAD; (4) histamine-producing cells accumulated in the spleens of aging Fas-deficient lpr/lpr mice. NK cells are an essential element in this process, not only because they express FasL in response to IL-12 plus IL-18, but also because they produce the cytokines IFNg and TNFa which are required to render basophil precursors susceptible to Fas/FasL interactions. Thus, the pro-inflammatory cytokines IL-12 and IL18 not only privilege the TH1 orientation of the immune response by inducing FasL, IFNg and TNFa, but limit the number of TH2 effector cells by promoting apoptosis of immature peripheral basophils, a potent source of histamine, IL-4 and IL-6 [158] (Fig. 3). Considering the increasing prevalence of allergic diseases in developed countries, several theories have been proposed to account for this progression. The most widely discussed is the so-called ‘‘hygiene hypothesis’’, which states that the confrontation with infections of the TH1 type may provide protection against future development of allergies. Even though this theory has been refuted in its original terms, it remains likely that the pattern of adult immune responses is determined by ‘‘danger’’ signals encountered in the past, even though they will not necessarily give rise to infections. Given the importance of basophils as effector cells in allergic reactions, it is interesting to note that a TH1 microenvironment can effectively diminish their immediate precursors and thus eventually attenuate the severity of this type of disease. 4.2. Histamine–cytokine connection during autoimmunity Bphs is one of the first non-major histocompatibility complex-linked genes shown to be involved in the susceptibility to multiple autoimmune diseases. It is located on mouse chromosome 6 and has recently been identified as H1R gene [159]. In experimental autoimmune orchitis (EAO) and experimental allergic encephalomyelitis (EAE) models, deletion of H1R gene leads to a delay in disease onset and a decrease in the severity of clinical signs when compared to wild type mice. Studies on T cell parameters show that EAE antigen-stimulated proliferation as well as antibody production is not significantly affected in H1 receptor-deficient mice. The key observation when comparing these mice with the wild type was a striking decrease in the production of IFNg, while IL-4 was increased. These data are consistent with the involvement of the H1 receptor in antigen-induced EAE, in which the T cell response in H1R/ mice, is biased towards TH2, which could be associated with a less severe pathology. Analysis of mRNA from multiple sclerosis lesions revealed increased

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Fig. 3. The development of TH1 cells hampers the onset of a TH2 response both through increased IFNg production and Fas-dependent apoptosis of cells belonging to basophil lineage, preventing their participation in allergic reactions (APC: antigen-presenting cell; HA: histamine; THp: T helper precursors).

amounts of H1R transcripts and its blockade by H1 receptor antagonists diminished EAE induction [160]. Most experimental data support the notion that proinflammatory reactions are preferentially induced or increased via the H1R, while inflammatory and immune responses are downregulated through the H2R. Even though this paradigm is still a matter of debate, it might be relevant to EAE since H2R agonists, such as dimaprit, significantly reduced clinical signs compared to vehicle in EAE mice [161]. However, paradoxically, H2R-deficient mice are also less sensitive to EAE induction because of their low TH1 effector cell response that results from a dysregulation of cytokine production by antigen-presenting cells. The latter produce less IL-12 and IL-6 and more MCP1 than their wild type or H1R-deficient counterpart [162]. Although further investigations are needed to understand in more detail how the interactions between H1R and H2R influence T cell polarization, the histamine–cytokine connection in autoimmunity has to be considered and provides new approaches of learning how pathogenic effector T cells emerge. Histamine levels are increased in plasma and tissues of streptozotocin (SPZ)-induced diabetic rats as well as in patients with diabetes mellitus. Recent studies in the mouse model suggest that hyperglycemia itself or hyperglycemiainitiated events are responsible both for enhancing HDC activity and for sensitizing to the action of LPS as HDC inducer [163].

that this mediator stimulated granulocyte precursors [165] when added during in vitro cultures, and we demonstrated after a couple of years that a similar positive effect on hematopoietic progenitors could be induced by endogenous histamine. Indeed, the latter is produced in response to IL-3 and GM-CSF in the hematopoietic microenvironment, where it is requisite for colony-forming units-spleen (CFU-S) cell cycling in response to IL-3 or GM-CSF plus IL-1 [166,167]. Since histamine is synthesized exclusively in response to hematopoietic growth factors generated during the immune response (IL-3, GM-CSF and IL-1), it is probably not needed for maintaining bone marrow homeostasis, but involved in inducible hematopoiesis, satisfying the increased requirements of an efficient host defense. It is therefore not surprising that in HDC-deficient mice only mast cells, which synthesize histamine constitutively, appear to be abnormal. In support of a positive effect of histamine on granulopoiesis, several reports have described side effects of some histamine receptor ligands. Rare cases of agranulocytosis have been described in response to cimetidine (H2 receptor antagonist) and clozapine (ligand of the H4 receptor). Some investigators have also proposed a participation of histamine in monocyte/macrophage differentiation, based on the observation that precursor cells of this lineage produce the mediator in response to M-CSF. These data should be confirmed and re-evaluated, as regards the implication of H4 receptors, the expression of which is most abundant in bone marrow, whatever the species.

4.3. Histamine–cytokine connection during hematopoiesis Byron, who reported in 1977 that exogenous histamine could promote the entry of CFU-S into cell cycle [164], was the first to propose a participation of histamine during hematopoiesis. About 10 years later, Nakaya et al. showed

4.4. Histamine–cytokine connection during anti-tumor response Studies on the production of histamine by tumors or by cells infiltrating tumors, on the one hand, and its effect on

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tumor growth, on the other hand, have produced numerous and often, conflicting results. The initial interest in histamine as a potential antitumor drug arose from experiments showing that induction of local anaphylaxis reduced the size of chemically induced fibrosarcomas. A number of experimental tumors have been shown to be sensitive to histamine, even though some adverse effects have also been recorded, which could be explained by different routes of administration and the nature of the tumor. Cimetidine, a H2R antagonist, has been largely investigated for its antiproliferative effect on tumor growth. Clinical trials have indicated that cimetidine could improve survival in gastric and colorectal cancer. The implication of H2R in this effect is highly probable. However, cimetidine is also a powerful radical scavenger when used at high concentrations. More recently, the implication of H2R has been proven, at least in the murine syngeneic experimental tumor, CT-26, a colon adenocarcinoma cell line. Indeed, in this model, low doses of cimetidine were efficient in diminishing tumor cell growth in vivo. This result could be ascribed to the immuno-modulating effect of the drug, more precisely to enhanced cytokine synthesis. Indeed, expression levels of cytokines known for their antitumor effect, such as lymphotoxin b, TNFa and IFNg are particularly low in this tumor because they are suppressed by histamine, which is produced by infiltrating cells. Blocking the H2R by its specific antagonist cimetidine can restore a normal production. The role of endogeneous histamine could be demonstrated in HDC/ mice where cimetidine no longer inhibited the proliferation of CT-26 cells. Transfection of tumor cells with the HDC gene restored the ability of cimetidine to suppress tumor cell growth and to normalize cytokine synthesis. In the same line of evidence, dimaprit, a H2 receptor agonist, significantly increased CT-26 tumor development [168,169]. Despite successful induction of chemotherapeutic remission, most patients with acute myeloid leukemia or chronic myeloid leukemia remain subject to recurrent and refractory disease. Among the strategies employed to prolong remission or survival, stimulation with IL-2 has been a therapeutic option to increase NK and T cell cytotoxicity against tumor cells. However, the efficiency of these agents has been less than what could be hoped for from in vitro experiments. The main reason for this low efficiency in vivo is that molecules produced by tumor cells themselves or by their microenvironment can modulate immune cell cytotoxicity. Monocytes-, granulocyte- or tumor cellderived reactive oxygen species (ROS) compose an essential part of these inhibiting signals by strongly decreasing the functions and the viability of NK cells. Knowing that histamine inhibits cell-mediated free radical production, the anti-tumoral efficiency of IL-2 or IFNa treatment in the presence of histamine dihydrochloride has been tested in patients suffering from various tumors, including AML [170]. Histamine can be safely co-administered with minimal side effect, and Phase III trials on metastatic melanomas have demonstrated a trend towards a superior survival

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benefit in patients receiving IL-2 plus histamine versus patients treated with IL-2 alone. A combined IL-2/histamine phase III trial in a population of AML patients is actually in progress. In CML, a similar treatment with histamine could alleviate oxidative stress, which decreases NK cell function during cancer immunotherapy. Indeed, apoptosis and dysfunction of these cytotoxic effectors in chronic myelogeneous leukemia result from ROS, the formation of which is inhibited by histamine in leukemic granulocytes. Since CML cells themselves contain histamine, a natural balance between ROS and histamine production could exist in CML. In this case, endogenous histamine could serve as an autocrine inhibitor of ROS, preventing inhibition and/or apoptosis of NK cells. However, it seems that the production of histamine is not sufficient, undoubtedly because NK cells deteriorate in function and in number during disease progression, suggesting a shift towards ROS production [171]. However, each time an immunotherapeutic effect is demanded during treatment of leukemia with cytokines or other molecules, a complementary administration of histamine should be considered.

5. Conclusion In the past few years, the interest in histamine research has been rekindled by many new data showing that this small molecule is produced by a variety of hematopoietic cells and can exert various regulatory functions during the immune response and hematopoiesis. This functional reevaluation of histamine has benefited from the development of new tools, such as HDC- or histamine receptor-deficient mice and new potent and specific agonists and antagonists of histamine receptors. The main concept emerging from these studies is that histamine participates in the cytokine network by establishing a cross-talk with some of its constituents. If certain data remain controversial, namely those concerning the role of histamine during TH1/TH2 differentiation, this is probably because of the complexity of the system, which involves several histamine receptor subtypes with distinct functions, the expression of which changes with the microenvironment and the differentiation stage of the cell. The recent discovery of the H4 receptor, which is preferentially expressed in hematopoietic and immunocompetent cells, has opened a new field of investigations. The functional characterization of this receptor and of the intracellular histamine-binding sites will most certainly change our present perception of the role of histamine in immunology and hematopoiesis.

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