title: The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils.
abstract: The histamine H4 receptor regulates the inflammatory response. However, it is not known whether this receptor has a functional role in human neutrophils. We found that fMLP (1 μM), but not histamine (0.1-1 μM), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 μM) or JNJ 28610244 (0.1-10 μM), a specific H4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 μM histamine and 10 μM JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H4 receptor antagonists. However, neither histamine nor the H4 receptor agonist JNJ 28610244 prevented fMLP-induced, Mac-1-dependent adhesion, indicating that the H4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H4 receptor by the selective agonist JNJ 28610244 blocked Mac-1-dependent activation of p38 MAPK, the kinase that controls neutrophil degranulation. We also show expression of the H4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation.
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Northern Ireland, United Kingdom; k.dib@qub.ac.uk.
authors.forename: Karim
authors.initials: K
authors.lastname: Dib
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia; Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic;
authors.forename: Tomas
authors.initials: T
authors.lastname: Perecko
authors.affiliation: Cancer Sciences Unit, University of Southampton, United Kingdom;
authors.forename: Veronika
authors.initials: V
authors.lastname: Jenei
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Northern Ireland, United Kingdom;
authors.forename: Cheryl
authors.initials: C
authors.lastname: McFarlane
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Northern Ireland, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Comer
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Northern Ireland, United Kingdom;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Brown
authors.affiliation: School of Biological and Biomedical Sciences, Durham University, United Kingdom; and.
authors.forename: Mwape
authors.initials: M
authors.lastname: Katebe
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Northern Ireland, United Kingdom;
authors.forename: Torsten
authors.initials: T
authors.lastname: Scheithauer
authors.affiliation: Janssen Research and Development, San Diego, California, USA.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.affiliation: School of Biological and Biomedical Sciences, Durham University, United Kingdom; and.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Chazot
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Northern Ireland, United Kingdom;
authors.forename: Madeleine
authors.initials: M
authors.lastname: Ennis
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000494:pharmacology; D005340:Fibrinogen; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010091:Oximes / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D011968:Receptors, Histamine / Q000502:physiology*; D000074040:Receptors, Histamine H4; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: C418607:HRH4 protein, human; D007211:Indoles; C000594390:JNJ28307474; C000591334:JNJ28610244; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D010091:Oximes; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D003571:Cytochalasin B; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006632:Histamine; D005340:Fibrinogen; D048051:p38 Mitogen-Activated Protein Kinases
keywords: inflammation; innate immunity; signaling