Abstract
Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.
Highlights
The biogenic amine histamine (2-(4-imidazolyl)-ethylamine) is a short-acting local mediator present in virtually all mammalian tissues
Crohn’s disease (CD) and ulcerative colitis (UC) differ regarding the immune response: while CD is largely associated with a Th1/Th17-dominated response, UC is mostly defined by a Th2-response [103,104,105]
Since histamine seemed to be functionally involved in gutphysiology, studies aimed at comprehensively identifying the histamine receptor subtypes expressed in the intestinal tract using tissues derived from different species [24,120,121,122,123]
Summary
The biogenic amine histamine (2-(4-imidazolyl)-ethylamine) is a short-acting local mediator present in virtually all mammalian tissues. Cells commonly known to produce histamine are mast cells and basophils [4,5], intestinal enterochromaffine-like cells [6], and histaminergic neuronal cells [7] These cells constitutively express HDC and produce histamine, which is bound to acidic polysaccharides such as heparin and stored in granules [8,9]. Piecemeal degranulation in mast cells is observed in diseased tissues and results in sustained presence of histamine, at lower concentration. Other cells, such as monocytes, dendritic cells, and T cells [12], produce significant amounts of histamine only during inflammatory reactions [13,14], which induce expression of HDC. [34] [35] [36,37,38,39,40,41,42,43,44,45,46,47] [48] [26,49,50,51,52,53,54,55,56,57,58,59] [23,26,60,61] [26,36,60,62,63] [64] [65,66] [67] [49,68,69] [26,38,49,60,70,71,72,73,74,75,76,77] [43,78,79]
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