Histamine and histidine decarboxylase: Immunomodulatory functions and regulatory mechanisms

Abstract

Histamine is a bioactive monoamine that is synthesized by the enzymatic activity of histidine decarboxylase (HDC) in basophils, mast cells, gastric enterochromaffin-like (ECL) cells and histaminergic neuronal cells. Upon a series of cellular stimuli, these cells release stored histamine, which elicits allergies, inflammation, and gastric acid secretion and regulates neuronal activity. Recent studies have shown that certain other types of myeloid lineage cells also produce histamine with HDC induction under various pathogenic stimuli. Histamine has been shown to play a series of pathophysiological roles by modulating immune and inflammatory responses in a number of disease conditions, whereas the mechanistic aspects underlying induced HDC expression remain elusive. In the present review, we summarize the current understanding of the regulatory mechanism of Hdc gene expression and the roles played by histamine in physiological contexts as well as pathogenic processes. We also introduce a newly developed histaminergic cell-monitoring transgenic mouse line (Hdc-BAC-GFP) that serves as a valuable experimental tool to identify the source of histamine and dissect upstream regulatory signals.

Keywords: bacterial artificial chromosome; histamine; histidine decarboxylase; transgenic mouse.

FIGURE 1

Primary function of histamine through the four types of histamine receptors

FIGURE 2

Accumulation of H3K4me1 (histone H3 lysine 4 monomethylation) and H3K27ac (histone H3 lysine 27 acetylation) in the gene body and flanking regions of the mouse Hdc locus on chromosome 2 in bone marrow (BM) and spleen (SP) cells. The data were obtained from the UCSC Genome Browser (http://genome.ucsc.edu)

FIGURE 3

The 293‐kb BAC clone (RP23‐40N15) containing all Hdc exons and 120 kb of 5′ and 148 kb of 3′ flanking sequence was modified by inserting GFP (green fluorescence protein) cDNA into the 1st exon. The mast cell‐ and basophil‐specific cis‐regulatory elements are located in proximity to the Hdc gene. Other myeloid lineage cell‐directed elements are located further than the 10‐kb upstream region

FIGURE 4

Examples of the pleiotropic functions of histamine produced in myeloid lineage cells