The role of histamine H4 receptor in immune and inflammatory disorders


Dr Ekaterini Tiligada, Department of Pharmacology, Medical School, University of Athens, M. Asias 75, GR-11527 Athens, Greece. E-mail:


Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H4 receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H4 receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H4 receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H4 as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H4 receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H4 receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders.






bone marrow


dendritic cell


G-protein-coupled receptor


H4 receptor-deficient mice


eosinophilic precursor cell line


inflammatory dendritic epidermal cells






selective H4 receptor antagonist


selective H4 receptor antagonist




mast cell


monocyte-derived IDEC


peripheral blood mononuclear cells


rheumatoid arthritis


signal transduction and activator of transcription


helper T cell


tumour necrosis factor-alpha


T regulatory cell


selective H4 receptor antagonist


Histamine [2-(4-imidazolyl)-ethylamine] is an endogenous short-acting biogenic amine synthesized from the basic amino acid histidine through the catalytic activity of the rate-limiting enzyme histidine decarboxylase and widely distributed throughout the body (Dy and Schneider, 2004). The pharmacological study of histamine started concurrently with its discovery by Sir Henry H Dale at the beginning of the 20th century (Barger and Dale, 1910; Dale and Laidlaw, 1910). One of the first described functions was its ability to mimic anaphylaxis and has since been demonstrated to play a major role in inflammatory processes. Following the recognition of its ‘somewhat complicated action’ by Dale and Laidlaw (1910), histamine has been one of the most studied substances in medicine for nearly a century, possessing a wide spectrum of activities (Figure 1) including its potent mediator role in immediate hypersensitivity reactions (Daugherty, 2004).

Figure 1.

Indicative major effects exerted by histamine. The predominant histamine receptors, designated H1, H2, H3 and H4, eliciting the effects are shown in parentheses.

Undoubtedly, the fundamental pleiotropic regulatory character of histamine in cellular events is attributed to its binding to four subtypes of G-protein-coupled receptors (GPCR), designated H1, H2, H3 and H4 (Figure 1) that are differentially expressed in various cell types (Dy and Schneider, 2004; Akdis and Simons, 2006; Chazot and Tiligada, 2008). Histamine receptor diversity is supported by pharmacological evidence and by the low protein sequence homology, which is suggestive of their evolution from different ancestral genes (Leurs et al., 2000). The H4 receptor shows little homology to the classical pro-inflammatory H1 receptor or the H2 receptor and about 35% homology with the H3 receptor. H3 and H4 receptors are most closely related to each other, and they have a closer phylogenetic relationship with peptide ligand GPCRs, while they are remotely related to other biogenic amine receptors, including H1 and H2 receptors (Nakayama et al., 2004).

Histamine is synthesized in several cell types of peripheral and central tissues, while its release from repository cells is modulated by a variety of stimuli. The classical source of histamine is the pluripotent heterogeneous mast cell (MC) (Riley and West, 1952), where it is stored in cytosolic granules and released by exocytosis to exert its immunomodulatory role in response to various immunological and non-immunological stimuli, including allergens, drugs, mechanical stimulation, cold, ultra violet rays and endogenous polypeptides such as substance P and bradykinin (Kakavas et al., 2006; Krishnaswamy et al., 2006). Non-MC histamine is derived from numerous sources, indicative examples being gastric enterochromaffin-like cells (Prinz et al., 2003), various types of blood cells, such as basophils (Falcone et al., 2006), macrophages, lymphocytes (Zwadlo-Klarwasser et al., 1994) and platelets (Masini et al., 1998), neurons (Arrang et al., 1983; Haas et al., 2008), chondrocytes (Maslinska et al., 2004) and tumours (Falus et al., 2001). In the gastric mucosa, enterochromaffin-like cell-derived histamine acts as a paracrine stimulant to control acid secretion in response to hormonal and neural stimuli (Prinz et al., 2003; Grandi et al., 2008). In the brain, histamine is synthesized exclusively in histaminergic neurons of the tuberomamillary nucleus of the posterior hypothalamus that project all over the central nervous system (Haas and Panula, 2003). In a mutual interaction network with other transmitter systems, brain histamine is implicated in basic homeostatic and higher brain functions, including sleep–wake regulation, circadian and feeding rhythms, immunity, learning and memory (Haas et al., 2008). Thus, in addition to the predominately H1 receptor-mediated actions on smooth muscle, vascular permeability and modulation of allergic responses, the main functions of histamine (Figure 1) include gastric acid secretion basically via H2 receptors (Black et al., 1972), neurotransmission in the central nervous system largely via H3 receptor signalling (Arrang et al., 1983; Haas et al., 2008) and modulation of immune system processes through the H1 receptor and the recently identified H4 receptor (Oda et al., 2000; Liu et al., 2001a; de Esch et al., 2005).

The histaminergic system has proved to be a rich source of drugs over the last five decades with a number reaching blockbuster status. H1 (commonly referred to as antihistamines) and H2 receptor antagonists are widely used in the treatment of allergy and gastrointestinal disorders, respectively, while H3 receptor antagonists may have therapeutic value in dementias, psychotic and sleep disorders as well as obesity (Hill et al., 1997). Most importantly, growing attention is directed towards the therapeutic exploitation of the H4 receptor in inflammation and cancer (Venable and Thurmond, 2006), following its cloning by several groups independently at the turn of the millennium (Nakamura et al., 2000; Oda et al., 2000; Cogéet al., 2001; Liu et al., 2001a; Morse et al., 2001; Nguyen et al., 2001; Zhu et al., 2001) and its subsequent characterization as the immune system histamine receptor.

Over the years, studies on the effect of histamine during the immune response have produced a number of apparently conflicting data. These inconsistencies might arise from the differential expression of histamine receptors that may vary with the experimental setup. The contribution of histamine receptors in immune responses is exemplified by the frequently stimulatory effects through H1 receptor and inhibitory actions through H2 receptor signalling, as well as by the regulatory role of these receptors in the balance between type I and II helper T (TH) cells (Dy and Schneider, 2004; Akdis and Simons, 2006). The localization of H4 receptors largely in haemopoietic cells, their distinct pharmacological profile and their role in chemotaxis and mediator release in various cell types (Nakamura et al., 2000; Oda et al., 2000; Liu et al., 2001a) led to the re-evaluation of many biological actions of histamine, resolved some of the inconsistencies regarding the pharmacology of histamine receptor ligands and differentiated its functional roles in physiology and pathophysiology (de Esch et al., 2005; Thurmond et al., 2008).

H4 receptor: the immune system histamine receptor

Histamine H4 receptor is a pertussis-toxin-sensitive GPCR predominantly expressed on cells of the immune system, including MCs, monocytes, eosinophils, dendritic cells (DCs), T cells and natural killer cells (Table 1); in peripheral tissues such as spleen, thymus, colon, blood leukocytes and bone marrow, its expression being induced or altered in response to inflammatory stimuli (Oda et al., 2000; Cogéet al., 2001; Liu et al., 2001a; Morse et al., 2001; Lippert et al., 2004; Gutzmer et al., 2005; Damaj et al., 2007; Dijkstra et al., 2007; 2008). The H4 receptor appears to have higher affinity for histamine compared with the H1 receptor, activation leading to leukocyte chemotaxis to sites of inflammation via Gαi/o proteins and increases in intracellular Ca2+ concentration (Hofstra et al., 2003; de Esch et al., 2005; Table 1). In addition to histamine, liver-expressed chemokine LEC/CCL16 has been reported to be a non-histamine endogenous H4 receptor agonist, demonstrating additive effects with histamine and involved in eosinophil trafficking (Nakayama et al., 2004).

Table 1.  Expression and functional characteristics of the histamine H4 receptor in cells associated with inflammatory and immune disorders
Cell typeH4 receptor expression, characteristics and functionReferences
  1. BM, bone marrow; DC, dendritic cell; HL60.15, eosinophilic precursor cell line; IDEC, inflammatory dendritic epidermal cells; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; MoDC, monocyte-derived DC; PBMC, peripheral blood mononuclear cells; STAT, signal transduction and activator of transcription; TH, helper T cell.

B-lymphocytesVery low expression level (human blood)Zhu et al. (2001)
Dendritic cellsmRNA expression; chemotaxis with Ca2+ fluxes (human blood)Zhu et al. (2001); Ling et al. (2004); Damaj et al. (2007)
Migration (guinea pig and mouse BM)Bäumer et al. (2008)
Up-regulation by IFN-γ; down-regulation of TH2-linked chemokine CCL2 and TH1 cytokine IL-12 (human IDECs)Dijkstra et al. (2008)
mRNA up-regulation during differentiation; suppression of IL-12p70 production; F-actin polymerization → migration (human MoDC)Gutzmer et al. (2005)
EosinophilsmRNA expression; intracellular Ca2+ mobilisation, actin polymerization, shape change, up-regulation of CD11b/CD18 and CD54 expression; migration into inflamed tissue (human blood)Oda et al. (2000); Morse et al. (2001); Buckland et al. (2003); Ling et al. (2004); Barnard et al. (2008)
Ca2+ mobilization, chemotaxis (mouse)O'Reilly et al. (2002)
FibroblastsmRNA up-regulation by LPS and indomethacin, protein levels increased by dexamethasone (human, dermal)Ikawa et al. (2008)
HL60.15 cell lineIL-5 induced differentiation → increased H4 receptor expressionLing et al. (2004)
Mast cellsH4 receptor mRNA and protein expression (human skin)Lippert et al. (2004)
Intracellular Ca2+ mobilization; chemotaxis without degranulation (mouse)O'Reilly et al. (2002); Hofstra et al. (2003); Thurmond et al. (2004)
Enhancement of CXCL12 chemotactic activity on mast cell precursors (human umbilical cord blood)Godot et al. (2007)
Local mast cell regulation, redistribution in ovalbumin-challenged oesophageal mucosal epithelium → infiltration of eosinophils (guinea pig)Yu et al. (2008)
MonocytesHigher expression in resting than in activated cells; up-regulation by IFN-γ; Ca2+ influx, down-regulation of CCL2 synthesis and release → reduced monocyte recruitment (human blood)Oda et al. (2000); Morse et al. (2001); Zhu et al. (2001); Dijkstra et al. (2007)
Natural killer cellsChemotaxis with no induction of Ca2+ mobilization (human blood)Damaj et al. (2007)
NeutrophilsExpression (human blood)Oda et al. (2000); Morse et al. (2001)
T-lymphocytesHigher expression in resting than in activated CD4+ and CD8+ cells; increased release of IL-16 from CD8+ cells (human, blood)Morse et al. (2001); Zhu et al. (2001); Gantner et al. (2002); Ling et al. (2004)
Suppression of STAT1α formation, phosphorylation and DNA binding (human non-atopic PBMCs); H4 receptor blockade → inhibition of STAT6 DNA binding (human atopic PBMCs)Horr et al. (2006); Michel et al. (2008)

The expression of the H4 receptor in several types of human immune cells and its chemotactic properties denote its role in immunomodulation (Figure 2, Table 1). Despite the interspecies differences in amino acid sequence, expression levels, ligand binding and receptor activation, the comparable tissue distribution suggests similar physiological roles for this receptor across the species (Liu et al., 2001b; Oda et al., 2005; Jiang et al., 2008).

Figure 2.

Indicative immunomodulatory actions of histamine that are mediated through histamine H4 receptors (H4) predominately expressed in immune cells. Gαi/o, G-protein; TH, helper T cell.

Eosinophil chemotaxis

Histamine was first described as a selective chemoattractant for eosinophils more than 30 years ago (Clark et al., 1975). In a retrospective literature evaluation, the reported histamine effects on eosinophil chemotaxis can now be attributed to the H4 receptor. The existence of a histamine receptor on the surface of eosinophils that was distinct from H1, H2 or H3 receptors and demonstrated low-affinity binding for R-(α)-methylhistamine antagonized by the H3/H4 antagonist thioperamide was hypothesized in 1994 (Raible et al., 1994). Concrete evidence that H4 receptors control leukocyte trafficking and pro-inflammatory responses was derived from the H4 receptor-mediated histamine-induced activation of eosinophils (Table 1), increased expression of adhesion molecules like CD11b/CD18(Mac1) and CD54(ICAM-1) and rearrangement of the actin cytoskeleton leading to eosinophil migration from the bloodstream into the sites of inflammation (O'Reilly et al., 2002; Buckland et al., 2003; Ling et al., 2004; Barnard et al., 2008).

Mast cell chemotaxis and chronic inflammation

Interestingly, human MCs constitutively express H4 receptors that govern autocrine and paracrine histamine-induced processes (Lippert et al., 2004). H4 receptor activation mediates chemotaxis and intracellular Ca2+ mobilization in murine MCs, without affecting degranulation, thus providing a mechanism for the selective recruitment of these effector cells into the tissues and the amplification of the histamine-mediated reaction eventually leading to chronic allergic inflammation (Hofstra et al., 2003). Supportive evidence for an autoregulatory function of the MC-expressed H4 receptor comes from its critical role in zymosan-induced recruitment of neutrophils in vivo, possibly via regulation of leukotriene B4 release from MCs (Takeshita et al., 2003; Thurmond et al., 2004), without however excluding the possibility of additional effects of other immune cells in the response (Liu et al., 2001b; Dunford et al., 2007).

Dentritic cell activation and T cell differentiation

The H4 receptor expressed on DCs, CD4+ and CD8+ T cells appears to control cytokine and chemokine production (Table 1). In general, histamine can enhance TH1 responses through H1 receptor activation and negatively regulate both TH1 and TH2 responses by acting on H2 receptors (Jutel et al., 2001). However, data concerning the differential expression of histamine receptor subtypes that mediate DC activation and TH1/TH2 differentiation have been somewhat contradictory (Dy and Schneider, 2004). The interest was revived after the identification of the H4 receptor, which alongside H1 and H2 receptors, modulates cytokine secretion during the integration of TH1/TH2 differentiation (Jutel et al., 2001). Cytokines mediate their effects via the signal transduction and activators of transcription (STAT), with STAT6 activation causing a shift towards the TH2 response implicated in allergic state development and STAT1 and STAT4 playing a role in the pathogenesis of asthma with distinct responses existing in non-atopic and atopic states. Histamine acting on the H4 receptor has been reported to suppress ex vivo the mitogen-induced STAT1 phosphorylation and its specific interaction with DNA in peripheral blood mononuclear cells derived from non-atopic individuals (Horr et al., 2006), while the H4 receptor antagonist JNJ7777120 inhibited STAT6 DNA binding in cells derived from atopic subjects (Michel et al., 2008). However, in mouse splenocytes, the H4 receptor exerted no effect on STAT4 (Liu et al., 2006) or STAT6 (Kharmate et al., 2007) phosphorylation.

Additional evidence for the immunomodulatory function of the H4 receptor is provided by its involvement in the release of the CD4+ cell chemoattractant interleukin (IL)-16 from human CD8+ T-lymphocytes in vitro (Gantner et al., 2002), the influence on mouse CD4+ T cell activation possibly via signalling in DCs (Dunford et al., 2006), as well as by its up-regulation during monocyte differentiation, suppression of IL-12p70 production and chemoattraction of human monocyte-derived DCs (Gutzmer et al., 2005). A reciprocal crosstalk between histamine and cytokines or chemokines involving the H4 receptor seems to be in operation. Interferon (IFN)-γ up-regulates H4 receptor expression in human peripheral blood monocytes/CD14+ (Dijkstra et al., 2007) and in inflammatory DCs from atopic dermatitis skin (Dijkstra et al., 2008). The H4 receptor-mediated induction of Ca2+ mobilization and down-regulation of synthesis and release of the TH2-linked chemokine CCL2 from monocytes is indicative of a negative feedback mechanism that would avoid the TH2 environment in case of high histamine levels in allergic inflammation and contribute to the shift to TH1 that is observed in the transition from acute to chronic allergic inflammation (Dijkstra et al., 2007). Comparably, H4 receptor stimulation down-regulates the production of the TH1 cytokine IL-12 and that of CCL2 in human monocyte-derived inflammatory dendritic epidermal cells, the latter leading to decreased monocyte migration (Dijkstra et al., 2008).

H4 receptor-mediated effects in inflammatory disorders

Histamine has long been known to mediate inflammatory, and allergic responses acting predominately through H1 receptors and H1 receptor antagonists have been used to treat allergies for many years (Hill et al., 1997). Accumulating evidence derived from diverse in vivo and in vitro studies using animal models of disease and human biological samples (Table 2) substantiates the fundamental role of the H4 receptor in histamine-induced chemotaxis of MCs, eosinophils and other immune cells (Thurmond et al., 2004; Ikawa et al., 2005; Dunford et al., 2006). In addition, the presence of H4 receptors mostly in immune system organs and their immunomodulatory role in cytokine production (Cogéet al., 2001; Gantner et al., 2002; Gutzmer et al., 2005) argue for the pathophysiological significance of H4 receptors in inflammatory conditions that are characterized by increases in immune cell numbers, such as asthma, allergic disorders and autoimmune diseases (Figure 3) and imply their contribution not only in the histamine-mediated initial inflammatory signal but also in the maintenance of inflammation (Thurmond et al., 2004; Kakavas et al., 2006; Dunford et al., 2007; Zhang et al., 2007; Table 2).

Table 2.  Evidence for the contribution of histamine H4 receptor to inflammatory disorders
ConditionFunction of the H4 receptorReferences
  1. 4-MH, 4-methylhistamine; Ag, antigen; BM, bone marrow; DC, dendritic cell; H4R−/−, H4 receptor-deficient mice; IDEC, inflammatory dendritic epidermal cells; IFN, interferon; IL, interleukin; JNJ10191584, selective H4 receptor antagonist; JNJ7777120, selective H4 receptor antagonist; MC, mast cell; Mo-IDEC, monocyte-derived IDEC; PBMC, peripheral blood mononuclear cells; STAT, signal transduction and activator of transcription; TH, helper T cell; TNF-α, tumour necrosis factor-alpha; VUF6002, selective H4 receptor antagonist.

Airway inflammationDecreased lung inflammation, lung eosinophil/lymphocyte infiltration and TH2 responses in H4R−/− and JNJ7777120-treated mice; decreased IL-4, IL-5, IL-13, IL-6, IL-17 levels upon ex vivo re-stimulation of mouse T cells → disrupted T cell functions; blockade of DC H4 receptors in vitro→ decreased cytokine and chemokine production → limited ability of DC to induce TH2 responses in murine T cellsDunford et al. (2006)
Intratracheal administration of H4 receptor agonist 4-MH before Ag challenge in a murine model of allergic asthma → reduced airway hyperreactivity and inflammation, increased IL-10 and IFN-γ and decreased IL-13 in the bronchoalveolar lavage fluid; accumulation of FoxP3+ T cellsMorgan et al. (2007)
In vitro stimulation of human T cells with H4 receptor agonist 4-MH → increased T cell migration skewed towards CD25- and intracellular FoxP3-expressing CD4+ cells; suppressed proliferation of autologous T cells dependent on IL-10 productionMorgan et al. (2007)
Increased H4 receptor expression in human nasal turbinate mucosa and nasal polyp tissue, tendency for correlation between H4 receptor expression and eosinophil cationic proteinJókúti et al. (2007)
Suppression of STAT1α formation and phosphorylation by H4 receptor agonist clobenpropit and enhancement of STAT1α levels, phosphorylation and DNA binding by JNJ7777120 in non-atopic human stimulated PBMCsHorr et al. (2006)
Inhibition of STAT6 DNA binding by JNJ7777120 in atopic human PBMCsMichel et al. (2008)
Inhibition of MC and eosinophil migration into oesophageal mucosal epithelium of sensitized guinea pigs by the H3/H4 receptor antagonist thioperamideYu et al. (2008)
Pruritus & dermatitisReduction of H4 receptor agonist clobenpropit-induced scratching by the H3/H4 receptor antagonist thioperamide in female Balb C miceBell et al. (2004)
No pruritic response with 4-MH in H4R−/− mice; attenuation of MC- or other haematopoietic cell-independent scratching by JNJ7777120 in miceDunford et al. (2007)
Strain differences between NMRI and Balb C mice in H4 receptor-mediated scratching, not associated with H4 receptor expression and protein levels in murine BM-derived DCs; clobenpropit-induced DC migration blocked by JNJ7777120Bäumer et al. (2008)
H4 receptor expression in skin IDECs, up-regulation by IFN-γ in Mo-IDECs; clobenpropit and 4-MH-induced down-regulation of CCL2 and IL-12 production in Mo-IDECs blocked by JNJ7777120 in human atopic dermatitisDijkstra et al. (2008)
Suppression of late-phase swelling and eosinophil infiltration by H3/H4 receptor antagonist thioperamide in Ag-non-specific dermatitis in miceHirasawa et al. (2008)
ArthritisVariable mRNA expression in synovial cells (superficial layer membrane, villi and vascular wall cells, fibroblast- and macrophage-like cells) from rheumatoid arthritis and osteoarthritis patientsIkawa et al. (2005); Grzybowska-Kowalczyk et al. (2007; 2008); Ohki et al., 2007
Increased cartilage histamine content without arthritis signs in JNJ7777120-treated rats with adjuvant arthritisZampeli et al. (2008)
Acute/subchronic inflammationReduction of early-phase paw oedema and thermal hyperalgesia by JNJ7777120 and VUF6002 in carrageenan-induced inflammation in ratsCoruzzi et al. (2007)
Reduced neutrophil release from BM and MC-dependent neutrophil recruitment by the H3/H4 receptor antagonist thioperamide in zymosan-induced peritonitis in miceTakeshita et al. (2003; 2004); Thurmond et al. (2004)
Reduction in macroscopic damage, mucosal and submucosal thickness and neutrophil infiltration and inhibition of colonic myeloperoxidase and TNF-α elevation by JNJ10191584 and JNJ7777120 in trinitrobenzene sulphonic acid-induced subchronic colitis in ratsVarga et al. (2005)
Increased conjunctival histamine content upon topical JNJ7777120 instillation in experimental conjunctivitis in ratsZampeli et al. (2009)
Ischaemia/reperfusion injuryH4 receptor stimulation → prevention of reperfusion injury development in the rat liverAdachi et al. (2006)
Figure 3.

Involvement of the histamine H4 receptor in a number of inflammatory disorders.

Consequently, the H4 receptor is currently an attractive target for the pharmacological modulation of histamine-transferred signals in inflammatory conditions (Buckland et al., 2003; Hofstra et al., 2003; de Esch et al., 2005; Bäumer et al., 2008) and for the development of beneficial therapeutic strategies for these conditions (Kiss et al., 2008; Thurmond et al., 2008). Furthermore, the use of H4 receptor-targeting agents in related studies, including JNJ7777120, the first highly selective H4 receptor antagonist developed (Jablonowski et al., 2003; Thurmond et al., 2004) and the potent selective agonist 4-methylhistamine (Lim et al., 2005), has provided useful information on the physiological role of histamine receptors in inflammatory conditions.

Airway inflammation and allergy

In inflammatory lung disorders, histamine acts as a mediator of both acute and chronic phases. Accumulating data support the function of histamine in cellular immunity through control of cytokine and chemokine production and migration of inflammatory cells, beyond its traditional role in mediating immediate airway hyper-responsiveness (Barnes et al., 1998). Although H1 receptor antagonists offer symptomatic relief in atopic nasal, conjunctival and skin disease, they are not optimally effective in asthma, where the contribution of each type of histamine receptor in histamine-mediated effects is currently subject to intense research. The H4 receptor is present in low amounts in the lung, where its expression in bronchial epithelial and smooth muscle cells and microvascular endothelial cells (Gantner et al., 2002) may contribute to the airway disease phenotypes in various ways.

The H4 receptor mediates redistribution and recruitment of MCs in the mucosal epithelium in response to allergens, thus amplifying allergic symptoms and maintaining chronic inflammation (Thurmond et al., 2004). Supportive evidence is derived from the H4 receptor-mediated synergistic sequential action of histamine and CXCL12, the chemokine that is constitutively expressed in skin and airway epithelium and plays a key role in allergic airway disorders, to induce migration of MC precursors in vitro (Godot et al., 2007). Moreover, the H4 receptor seems to regulate only locally MC redistribution in the oesophageal mucosal epithelium followed by infiltration of eosinophils in ovalbumin-challenged guinea pigs (Yu et al., 2008).

The reduced lung inflammation and the decreases in TH2 responses observed in H4 receptor-deficient (H4R−/−) mice and upon oral gavage administration of selective antagonists in a murine model of allergic airway inflammation documented the role of the H4 receptor in modulating TH2 allergic responses, by influencing CD4+ T cell activation attributed to decreased cytokine and chemokine production by DCs (Dunford et al., 2006). In another study, inhibition of airway resistance and inflammation, mediated through the recruitment of CD25+FoxP3+ T regulatory (Treg) cells was observed by using the selective H4 receptor agonist 4-methylhistamine administered intratracheally into the lungs of asthmatic mice (Morgan et al., 2007). The beneficial actions of both H4 agonists and antagonists observed in asthmatic mice were attributed to the local versus systemic administration of the compounds, respectively, and to the resulting concentration gradient within the lung in the former case that would allow the migration of the immune response suppressive Treg cells (Morgan et al., 2007).

Considering the role of the H4 receptor in the modulation of the asthmatic response revealed by these studies and the reported inhibitory effect of H4 receptor agonists on antigen-specific responses in human peripheral blood mononuclear cells and T cell lines, which, however, was not reversed by the H3/H4 receptor antagonist thioperamide (Sugata et al., 2007), additional data are a prerequisite imperative of providing conclusive evidence concerning the optimal therapeutic exploitation of H4 receptor ligands in chronic airway disease (Daugherty, 2004). Furthermore, species and strain differences should be considered carefully before data interpretation as murine DC chemotactic response needs very high histamine concentrations to be observed (Bäumer et al., 2008) and different cytokine secretion patterns are observed in H4R−/− mice and murine DCs (Dunford et al., 2006).

Chronic pruritus

Chronic pruritus is a common clinical condition associated with cutaneous or systemic disease and although histamine, MCs and basophils are increased in patients, classical H1 receptor antagonists are of limited use due to lack of effectiveness (O'Donoghue and Tharp, 2005). Histamine has been shown to induce scratching in Balb C mice via H4 receptors (Bell et al., 2004). Treatment of mice with JNJ7777120 attenuated the pruritic response to histamine, IgE and compound 48/80, the inhibitory effect of the H4 receptor antagonist being greater than that observed with H1 receptor antagonists (Dunford et al., 2007). Even so, H1 receptor-mediated actions seem to complement the H4 receptor-mediated enhanced DC migration through skin, and therefore H1 combined with H4 receptor antagonists could be a beneficial approach (Bäumer et al., 2008; Roßbach et al., 2009). In addition, although H4 receptor antagonism strongly attenuated the pruritic response to the classical contact allergen 2,4-dinitrochlorobenzene and to the respiratory chemical allergen toluene-2,4-diisocyanate, which mediate TH1- and TH2-dominated inflammation, respectively, JNJ7777120 failed to reduce the allergic inflammatory response associated with allergic dermatitis (Roßbach et al., 2009).

Although H4 receptors are expressed in human skin MCs (Lippert et al., 2004), inflammatory dendritic epidermal cells (Dijkstra et al., 2008) and dermal fibroblasts (Ikawa et al., 2008), the H4 receptor-mediated pruritus was suggested to be MC-independent and possibly coupled to actions on the peripheral terminals of sensory neurons rather than to effects on haemopoietic cells (Dunford et al., 2007). However, before extrapolating these results to human pathophysiology that may lead to misinterpretation of the complex regulatory MC-DC interactions, one should consider the pharmacological differences in agonist affinity between human and mouse H4 receptors. Results from functional studies in experimental animals need cautious interpretation as species differences certainly occur. Indeed, detailed site-directed mutagenesis data reported recently demonstrated Phe169 in the second extracellular loop as the single amino acid responsible for the differences in agonist affinity between the human and mouse H4 receptors (Lim et al., 2008). Moreover, strain differences in the mouse response to the H4 receptor agonist/H3 receptor antagonist clobenpropit were recently reported, NMRI mice being more susceptible to H4 receptor-induced itching compared with Balb C mice (Bäumer et al., 2008).

Autoimmune disorders

Histamine has been recognized to play a role in autoimmune diseases, including rheumatoid arthritis (RA) that is characterized mainly by synovial tissue inflammation leading to erosion and destruction of articular cartilage with subsequent joint deformity (Woolley and Tetlow, 1997). Although a recent report argued for the anti-inflammatory properties of histamine in RA (Adlesic et al., 2007), the amine has been largely regarded as a pro-inflammatory mediator in arthritic disease (Maslinska et al., 2004; Grzybowska-Kowalczyk et al., 2007; 2008; Ohki et al., 2007). Besides the presence of H1 and H2 receptors, the considerable variations in H4 receptor expression in human synovial cells could be related to RA severity and duration (Ikawa et al., 2005). The localization of H4 receptors in synovial and vascular wall cells of patients with RA (Grzybowska-Kowalczyk et al., 2007) and osteoarthritis (Grzybowska-Kowalczyk et al., 2008) and the identification of H4 receptors in fibroblast- and macrophage-like cells from RA synovial tissues (Ohki et al., 2007) further support the contribution of the receptor in the pathophysiology of the disease. Moreover, evidence for the systemic contribution of histamine in the arthritic phenotype was obtained by using a rat model of adjuvant arthritis, and a functional role of the H4 receptor in the normal cartilage has been suggested in the rat, raising attractive questions regarding the H4 receptor-mediated mechanisms in this tissue (Zampeli et al., 2008).

Other inflammatory conditions

The association of the H4 receptor with immune cell function motivated the intense investigation of its implication in virtually every condition that comprises an inflammatory component (Figure 3), mostly using either the mixed H3/H4 receptor antagonist thioperamide or selective H4 receptor agonists and antagonists (Zhang et al., 2007). Thus, H4 receptor agonists prevented the development of reperfusion injury following ischaemia-induced liver damage (Adachi et al., 2006). Beneficial actions of the H4 receptor antagonists have been reported in a rat model of subchronic colitis (Varga et al., 2005) and in MC-dependent mouse models of zymosan-induced pleurisy or peritonitis (Takeshita et al., 2003; Thurmond et al., 2004), used as an experimental model of acute inflammation involving neutrophil recruitment from the bone marrow (Takeshita et al., 2004).

On the other hand, H4 receptor antagonists exerted an inhibitory effect on airway inflammation (Dunford et al., 2006) and pruritic responses (Dunford et al., 2007) in MC-deficient mice but they were not effective in MC-independent mouse models of acute inflammation, such as histamine-induced paw oedema, thioglycollate-induced peritonitis (Thurmond et al., 2004) and carrageenan-induced neutrophilia (Takeshita et al., 2003). In a rat model of carrageenan-induced acute inflammation and pain, H4 receptor antagonists reduced the early phase development of oedema but not the late inflammatory responses and attenuated the hyperalgesic response to thermal stimuli, possibly acting through peripheral nociceptive pathways (Coruzzi et al., 2007).

In addition to the localization of H4 receptors in synovial specimens from RA patients (Ikawa et al., 2005; Grzybowska-Kowalczyk et al., 2007; 2008; Ohki et al., 2007), a limited number of studies have attempted to identify H4 receptor alterations in human samples derived from inflamed tissues. For instance, the increased levels of H4 receptors in normal nasal turbinate mucosa and in nasal polyp tissue and the tendency for correlation between the expression of H4 receptors and eosinophil cationic protein led to the speculation that the receptor may have a role in mediating histamine effects and eosinophil accumulation and activation in nasal and paranasal sinus mucosa inflammatory diseases (Jókúti et al., 2007).

These results certainly reflect the complex cellular and biochemical networks orchestrating inflammation. However, species differences in H4 receptor-mediated responses and/or ligand efficacy need to be elucidated before decisive conclusions are drawn regarding the use of H4 receptor ligands in the treatment of inflammatory human disease. In addition, yet unidentified receptor polymorphisms must also be taken in consideration. The first two alternatively spliced H4 receptor isoforms, which have a dominant negative effect on the full-length H4 receptor functionality by retaining it intracellularly and inactivating it presumably via hetero-oligomerization, have been cloned in CD34+ cord blood-cell-derived eosinophils and MCs (van Rijn et al., 2008).

Future perspectives

Although histamine has not been ignored by immunopharmacologists for nearly a century, the discovery of the H4 receptor offered to the amine a new perspective beyond its traditional pharmacological properties. The complexity of leukocyte immune surveillance, trafficking and recruitment and the plethora of different effects exerted by histamine through a repertoire of four receptor subtypes make hard to predict the overall effect of H4 receptors in inflammatory conditions at present. H4 receptor antagonists may be effective candidates in treating diseases associated with chronic pruritus and asthma, without disregarding the potential clinical application of H4 receptor ligands in autoimmune diseases like RA. A number of candidate drugs targeting the H4 receptor are in preclinical assessment for a range of inflammatory disorders; some showing promise for potential entry into clinical trials and even though the available data are variable in quality, they are adequate in quantity to justify an optimistic perspective for this new drug target.

Conflict of interest

The authors state no conflict of interest.