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.

• MeSH
• Leukemia, Promyelocytic, Acute pathology   MeSH
• Lymphocyte Function-Associated Antigen-1 chemistry   MeSH
• Cell Adhesion drug effects   physiology   MeSH
• Cytochalasin B pharmacology   MeSH
• Cell Degranulation * drug effects   MeSH
• Fibrinogen MeSH
• Histamine pharmacology   MeSH
• Indoles pharmacology   MeSH
• Protein Conformation drug effects   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Macrophage-1 Antigen physiology   MeSH
• MAP Kinase Signaling System drug effects   MeSH
• RNA, Messenger biosynthesis   genetics   MeSH
• p38 Mitogen-Activated Protein Kinases physiology   MeSH
• N-Formylmethionine Leucyl-Phenylalanine pharmacology   MeSH
• Cell Line, Tumor MeSH
• Neutrophils drug effects   physiology   MeSH
• Oximes pharmacology   MeSH
• Piperazines pharmacology   MeSH
• Piperidines pharmacology   MeSH
• Pyridines pharmacology   MeSH
• Receptors, Histamine physiology   MeSH
• Receptors, G-Protein-Coupled agonists   antagonists & inhibitors   physiology   MeSH
• Cell Shape drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH