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The human histamine H4 receptor (H4R) is a Gαi/o-coupled receptor which is mainly expressed on hematopoietic cells. Accordingly, the receptor is implicated in the pathology of various diseases such as autoimmune disorders, bronchial asthma and pruritus. Due to complicated receptor pharmacology, the lack of a reliable antibody and limited availability of primary cells expressing the receptor the physiology of this receptor is still poorly understood. Therefore, we aimed to assess absolute receptor mRNA expression and functionality (intracellular Ca(2+) release) in various human myeloid cell types such as granulocytes, monocytes, macrophages and dendritic cells (DCs). This was put into context with the expression of the H1R and H2R. In addition, the influence of various inflammatory stimuli on H4R expression was investigated in macrophages and monocyte-derived DCs. We found that classically activated macrophages treated with pro-inflammatory stimuli down-regulated histamine receptor mRNA expression as did LPS and zymosan A matured monocyte-derived DCs. In contrast, alternatively activated macrophages (IL-4 or IL-13) upregulated H2R and H4R expression compared to controls. Consistent with existing literature, we found eosinophils to be the major source of the H4R. Since availability of primary eosinophils is limited, we developed a cell model based on the differentiated eosinophilic cell line EOL-1, in which H4R pharmacology and physiology may be studied., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Because of their favourable safety profile and beneficial anti-inflammatory properties, the CysLT1 receptor antagonists (LTRA), montelukast, zafirlukast and pranlukast are approved for the treatment of asthma and are frequently prescribed as add-on therapeutics to reduce the amount of inhaled glucocorticoids and β2-agonists. There is evidence that some of these anti-inflammatory properties might be of a secondary nature and therefore, unrelated to the CysLT1 antagonism. Here, we show that LTRA inhibit PGE2 formation in cytokine-stimulated Hela and A549 carcinoma cells and in lipopolysaccharide (LPS)-stimulated human leukocyte preparations (IC50∼20μM). Neither expression of enzymes involved in PGE2 synthesis nor arachidonic acid release and COX activities were inhibited by the compounds. In contrast, mPGES-1 activity was suppressed at low micromolar levels (IC50 between 2 and 4μM). This suppression was specific for PGE2 synthesis, since PGD2 and PGI2 levels in LPS-stimulated leukocyte preparations were not negatively affected. PGF2α levels were concomitantly inhibited, probably due to its direct synthesis from PGE2. Several major conclusions can be drawn from this study: (A) clinical trials investigating elevated doses of the compounds are helpful to confirm suppression of PGE2 synthesis in vivo; (B) studies investigating the role of CysLTs in cell culture or animal models of inflammation and cancer have to be reassessed carefully, if higher doses of LTRA were applied or serum levels in cell culture assays were low; and (C) LTRA may serve as new scaffolds for the development of potent, selective and well tolerated mPGES-1 inhibitors., (Copyright © 2013 Elsevier Inc. All rights reserved.)