Background and purpose: Since the identification of the histamine H₄ receptor, several ligands activating this receptor have been described and more compounds are in development. These ligands are well characterized in pharmacological assays, including radioligand competition binding studies, GTPγS and GTPase assays. In most cases, these experiments are performed in transfected cell lines, expressing unnaturally high levels of target receptors and G-protein signalling components. In this study we investigated the specific properties of H₄ receptor ligands in native cells.
Experimental approach: Histamine and five different H₄ receptor agonists - 4-methylhistamine, UR-PI376, clobenpropit, VUF8430 and ST-1006 - were characterized in freshly isolated human monocytes. The ligands (10 nM-10 μM) were tested as inhibitors of IL-12p70 secretion from human monocytes and the effects of the H₂ receptor antagonist ranitidine and the H₄ receptor antagonist JNJ7777120 on their action was investigated.
Key results: Histamine and all the tested agonists reduced IL-12p70 secretion into monocyte supernatants by 40-70%. The potencies varied with pEC50 values ranging from 5.7 to 6.9, depending on the agonist used. All potencies were lower than those determined in the original investigations of the compounds. Pretreatment of monocytes with H₂ or H₄ receptor antagonists showed that some H₄ receptor ligands also had low activity at the H₂ receptor.
Conclusions and implications: Our study demonstrates discrepancies between the potencies obtained from assays in transfected cell lines and assays in native human cells, indicating the importance of evaluating H₄ receptor ligands in native cells.
Keywords: 4-methylhistamine; ST-1006; UR-PI376; VUF8430; clobenpropit; histamine; histamine H4 receptor.
© 2013 The British Pharmacological Society.