A Potent and Selective Histamine H<sub>4</sub>Receptor Antagonist with Anti-Inflammatory Properties

Thurmond, Robin L.; Desai, Pragnya J.; Dunford, Paul J.; Fung-Leung, Wai-Ping; Hofstra, Claudia L.; Jiang, Wen; Nguyen, Steven; Riley, Jason P.; Sun, Siquan; Williams, Kacy N.; Edwards, James P.; Karlsson, Lars

doi:10.1124/jpet.103.061754

Cited by 348 publications

(401 citation statements)

References 32 publications

(47 reference statements)

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“…The function of histamine in cellular immunity, through the control of cytokine and chemokine production and migration of inflammatory cells, beyond its traditional role in mediating fast airway hyper-responsiveness, has been defined [40]. In a mouse model of zymosan-induced peritonitis, histamine H 4 R ligands exerted anti-inflammatory activity [41,42]. In this model, intra-peritoneal treatment of mice with zymosan induces neutrophil migration, which is blocked by an H 4 R antagonist [43].…”

Section: Discussionmentioning

confidence: 99%

Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

Lucarini

Pini

Rosa

et al. 2016

Pharmacological Research

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Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The results here reported clearly demonstrated that H 4 R ligands have a beneficial effect in a model of lung fibrosis in the mouse, thus indicating that H 4 R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases.4

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Section: Discussionmentioning

confidence: 99%

Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

Lucarini

Pini

Rosa

et al. 2016

Pharmacological Research

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“…Furthermore, we studied immunologic and chemotactic effects and signal transduction pathways on human MoDC by using the stimuli mentioned above and by using additional substances that allow the dissection of H3R and H4R signaling, i.e., clobenpropit, an antagonist of the H3R and an agonist of the H4R, allowing the dissection of H3R and H4R function (6,17,20,22), ciproxifan, an antagonist of the H3R (23)(24)(25), and JNJ7777120, an antagonist of the H4R (24,26,27).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

Gutzmer

Diestel

Mommert

et al. 2005

The Journal of Immunology

220

249

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There is increasing evidence that histamine as an important mediator of immediate type allergic reactions also effects professional APCs. Recent reports showed effects of histamine on human monocyte-derived dendritic cells (MoDC) mediated primarily via histamine H1 receptors (H1R) and H2R. We show here that MoDC also express H3R and H4R at the mRNA and protein level. mRNA of the H3R is down-regulated and mRNA of the H4R is up-regulated during the differentiation from monocytes to MoDC. H4R or H2R stimulation suppressed IL-12p70 production in MoDC. Induction of cAMP was necessary for IL-12p70 inhibition mediated via the H2R. In contrast, H4R stimulation did not affect cAMP production but induced the transcription factor AP-1, and U0126, an inhibitor of AP-1 transactivation and MEK, rescued H4R mediated IL-12p70 suppression. Moreover, MoDC responded to a H4R agonist (and also to a H2R agonist) with increased F-actin polymerization and migration in modified Boyden chamber assays, suggesting a chemotactic effect of histamine via the H2R and the H4R. Thus, H4R stimulation on MoDC results in immunomodulatory and chemotactic effects. Histamine induces chemotaxis and IL-12p70 suppression via different receptors using different signaling pathways, which might be important for the pathogenesis of and therapeutic interventions in allergic diseases.

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“…Moreover, during receptor. [19,37] Moreover, at least some antagonism by thioperamide, JNJ7777120 and MMPCI would have been expected at the H 4 receptor [19,35] even though histamine was used with a much higher concentration than its affinity for the H 4 receptor subtype [19]. In previous studies evaluating the H 4 receptor-mediated effects of histamine on eosinophils, the A c c e p t e d m a n u s c r i p t effects of similar histamine concentrations were antagonized with similar thioperamide and JNJ7777120 concentrations and agonized with similar clobenpropit concentrations as used in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…To further investigate the role of the H 4 -subtype, the effect of JNJ7777120, a recently described selective histamine H 4 receptor antagonist (K i ~ 4 nM) [35] was studied on human eosinophil apoptosis in the absence and presence of histamine and IL-5. At concentrations of JNJ7777120 up to 500 nM, apoptosis of human eosinophils was unaffected (Fig.…”

Section: The Histamine H 4 Receptor Subtypementioning

confidence: 99%

Histamine reverses IL-5-afforded human eosinophil survival by inducing apoptosis: Pharmacological evidence for a novel mechanism of action of histamine

Hasala¹,

Giembycz²,

Janka-Junttila³

et al. 2008

Pulmonary Pharmacology & Therapeutics

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A c c e p t e d m a n u s c r i p tCaspase activities were assessed by using commercial Caspase-Glo ® 3/7, 8, and 9 luminescence assays.Histamine (10-100 µM) partially reversed IL-5-induced human eosinophil survival by enhancing apoptosis as assessed by measuring the relative DNA content of PI-stained cells.This effect was not mediated through any of the known histamine receptors or through nonspecific activation of 5-hydroxytryptamine receptors or α-adrenoceptors. Moreover, the reversal of IL-5-inhibited eosinophil apoptosis by histamine seemed not to utilize the conventional intracellular second messenger pathways including cyclic AMP, protein kinase A or phospholipase C. Inhibition of caspase 6 and caspases 1, 10 or 12 reversed the effects of histamine but also inhibited apoptosis in general.In conclusion, the data presented herein indicate that histamine induces human eosinophil apoptosis in the presence of a survival-prolonging cytokine by a mechanism that does not apparently involve the activation of any of the currently known histamine receptor subtypes.The possibility exists that another, as yet unidentified, histamine receptor may exist in human eosinophils that regulates survival, although the participation of histamine receptorindependent mechanisms cannot be excluded. 3A c c e p t e d m a n u s c r i p t

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A Potent and Selective Histamine H₄Receptor Antagonist with Anti-Inflammatory Properties

Cited by 348 publications

References 32 publications

Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

Histamine reverses IL-5-afforded human eosinophil survival by inducing apoptosis: Pharmacological evidence for a novel mechanism of action of histamine

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A Potent and Selective Histamine H4Receptor Antagonist with Anti-Inflammatory Properties

Cited by 348 publications

References 32 publications

Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

Histamine reverses IL-5-afforded human eosinophil survival by inducing apoptosis: Pharmacological evidence for a novel mechanism of action of histamine

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A Potent and Selective Histamine H₄Receptor Antagonist with Anti-Inflammatory Properties