Histamine-cytokine connection in immunity and hematopoiesis

A number of recent studies have led to a reappraisal of the functional capacities of histamine in immunity and hematopoiesis. This change of perspective was provided by the following findings: (1) the evidence for multiple cellular sources of histamine, differing from mature basophils and mast cells by their ability to newly synthesize and liberate the mediator without prior storage, (2) the discovery of a novel histamine receptor (H4R), preferentially expressed on hematopoietic and immunocompetent cells, (3) the potential intracellular activity of histamine through cytochrome P450 and (4) the demonstration of a histamine-cytokine cross-talk. Indeed, cytokines not only modulate the degranulation process of histamine but also control its neosynthesis by the histamine-forming enzyme, histidine decarboxylase (HDC), at transcriptional and post-transcriptional levels. In turn, histamine intervenes in the intricate cytokine network, regulating cytokine production by immune cells through distinct receptors signaling distinct biological effects. This type of regulation is particularly relevant in the context of TH1/TH2 differentiation, autoimmunity and tumor immunotherapy.