The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils

The histamine H-4 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 mu M), but not histamine (0.1-1 mu M), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 mu M) or JNJ 28610244 (0.1-10 mu M), a specific H-4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 mu M histamine and 10 mu M JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H-4 receptor antagonists. However, neither histamine nor the H-4 receptor agonist JNJ 28610244 prevented fMLP-induced, Mac-1-dependent adhesion, indicating that the H-4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H-4 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 H-4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H-4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation.