Abstract
The most recently characterized H4 histamine receptor (H4R) is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs.
Highlights
Histamine is one of the most versatile biogenic amines with pleiotropic activities, including regulatory functions during the immune response and hematopoiesis [1,2,3]
We evaluated the function of the H4R, by examining the effect of histamine, its natural ligand, and clobenpropit (CB), one of its most potent agonists, on the cell cycle status of sorted c-kit+ bone marrow (BM) cells, which comprise a heterogenous population of progenitors at various differentiation stages
In this study we provide the first demonstration that the H4R is expressed in murine and human hematopoietic progenitor cells and that its activation results in the inhibition of growth factorinduced cell cycling
Summary
Histamine is one of the most versatile biogenic amines with pleiotropic activities, including regulatory functions during the immune response and hematopoiesis [1,2,3]. Its most clearly established functions consist in recruitment and activation of hematopoietic cells involved in inflammatory responses, such as eosinophils, mast cells, neutrophils and dendritic cells [10,11,12,13,14]. Because of these activities, together with H4R-induced IL-16 production by CD8 cells [15] and alleviation of experimental allergic asthma in H4R-deficient mice [16], this receptor is considered a potential pharmacological target for anti-inflammatory therapy [17]
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