Histamine has a key role in allergic inflammatory conditions. The inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists--commonly known as antihistamines--have been used to treat allergies for many years. However, the importance of histamine in the pathology of conditions such as asthma and chronic pruritus may have been underestimated. Here, we review accumulating evidence suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions.
The diverse physiological functions of histamine are mediated through distinct histamine receptors. Mast cells are major producers of histamine, yet effects of histamine on mast cells are currently unclear. The present study shows that histamine induces chemotaxis of mouse mast cells, without affecting mast cell degranulation. Mast cell chemotaxis toward histamine could be blocked by the dual H 3 /H 4 receptor antagonist thioperamide, but not by H 1 or H 2 receptor antagonists. This chemotactic response is mediated by the H 4 receptor, because chemotaxis toward histamine was absent in mast cells derived from H 4 receptor-deficient mice but was detected in H 3 receptor-deficient mast cells. In addition, Northern blot analysis showed the expression of H 4 but not H 3 receptors on mast cells. Activation of H 4 receptors by histamine resulted in calcium mobilization from intracellular calcium stores. Both G␣i/o proteins and phospholipase C (PLC) are involved in histamineinduced calcium mobilization and chemotaxis in mast cells, because these responses were completely inhibited by pertussis toxin and PLC inhibitor 1- [6-[[17-3-methoxyestra-1,3,5 (10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122). In summary, histamine was shown to mediate signaling and chemotaxis of mast cells via the H 4 receptor. This mechanism might be responsible for mast cell accumulation in allergic tissues.
The histamine H 4 receptor (H 4 R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H 4 R agonists have not been identified. In the present study, we therefore evaluated the human H 4 R (hH 4 R) for its interaction with various known histaminergic ligands. Almost all of the tested H 1 R and H 2 R antagonists, including several important therapeutics, displaced less than 30% of specific [3 H]histamine binding to the hH 4 R at concentrations up to 10 M. Most of the tested H 2 R agonists and imidazolebased H 3 R ligands show micromolar-to-nanomolar range hH 4 R affinity, and these ligands exert different intrinsic hH 4 R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H 4 R ligand (K i ϭ 50 nM) that has a Ͼ100-fold selectivity for the hH 4 R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH 4 R (pEC 50 ϭ 7.4 Ϯ 0
Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H 4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo.
Histamine is an important inflammatory mediator that is released in airways during an asthmatic response. However, current antihistamine drugs are not effective in controlling the disease. The discovery of the histamine H4 receptor (H4R) prompted us to reinvestigate the role of histamine in pulmonary allergic responses. H4R-deficient mice and mice treated with H4R antagonists exhibited decreased allergic lung inflammation, with decreases in infiltrating lung eosinophils and lymphocytes and decreases in Th2 responses. Ex vivo restimulation of T cells showed decreases in IL-4, IL-5, IL-13, IL-6, and IL-17 levels, suggesting that T cell functions were disrupted. In vitro studies indicated that blockade of the H4R on dendritic cells leads to decreases in cytokine and chemokine production and limits their ability to induce Th2 responses in T cells. This work suggests that the H4R can modulate allergic responses via its influence on T cell activation. The study expands the known influences of histamine on the immune system and highlights the therapeutic potential of H4R antagonists in allergic conditions.
1 During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H 4 but not H 3 receptors. The possible effects of histamine on eosinophils and the receptor mediating these effects were investigated in our studies. 2 Histamine (0.01-30 mM) induced a rapid and transient cell shape change in human eosinophils, but had no effects on neutrophils. The maximal shape change was at 0.3 mM histamine with EC 50 at 19 nM. After 60 min incubation with 1 mM histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01-1 mM) also enhanced the eosinophil shape change induced by other chemokines. 3 Histamine-induced eosinophil shape change was mediated by the H 4 receptor. This effect was completely inhibited by H 4 receptor-specific antagonist JNJ 7777120 (IC 50 0.3 mM) and H 3 /H 4 receptor antagonist thioperamide (IC 50 1.4 mM), but not by selective H 1 , H 2 or H 3 receptor antagonists. H 4 receptor agonists imetit (EC 50 25 nM) and clobenpropit (EC 50 72 nM) could mimic histamine effect in inducing eosinophil shape change. 4 Histamine (0.01-100 mM) induced upregulation of adhesion molecules CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on eosinophils. This effect was mediated by the H 4 receptor and could be blocked by H 4 receptor antagonists JNJ 7777120 and thioperamide. 5 Histamine (0.01-10 mM) induced eosinophil chemotaxis with an EC 50 of 83 nM. This effect was mediated by the H 4 receptor and could be blocked by H 4 receptor antagonists JNJ 7777120 (IC 50 86 nM) and thioperamide (IC 50 519 nM). Histamine (0.5 mM) also enhanced the eosinophil shape change induced by other chemokines. 6In conclusion, we have demonstrated a new mechanism of eosinophil recruitment driven by mast cells via the release of histamine. Using specific histamine receptor ligands, we have provided a definitive proof that the H 4 receptor mediates eosinophil chemotaxis, cell shape change and upregulation of adhesion molecules. The effect of H 4 receptor antagonists in blocking eosinophil infiltration could be valuable for the treatment of allergic diseases. The histamine-induced shape change and upregulation of adhesion molecules on eosinophils can serve as biomarkers for clinical studies of H 4 receptor antagonists.
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