Genetic Deficiency of the Histamine H4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice

Schirmer, Bastian; Rother, Tamina; Bruesch, Inga; Bleich, André; Werlein, Christopher; Jonigk, Danny; Seifert, Roland; Neumann, Detlef

doi:10.3390/cancers12040912

Cited by 8 publications

(4 citation statements)

References 51 publications

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“…Using mouse models for colitis and colitis-associated colon carcinoma in combination with genetic and pharmacological manipulation, we previously demonstrated the involvement of H 4 R in the respective pathologies (Schirmer et al 2015(Schirmer et al , 2020b. Moreover, we were able to ascribe H 4 R-mediated histamine function to normal mouse colon epithelial cells (Schirmer et al 2020a).…”

Section: Introductionmentioning

confidence: 84%

Histamine H1- and H4-receptor expression in human colon-derived cell lines

Schrammel,

König,

Frommer

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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In previous studies, we demonstrated the involvement of H4R in inflammatory bowel disease (IBD) and IBD-associated colon cancer in mice and could ascribe H4R-mediated histamine function to colon epithelial cells. The transferability of obtained data to humans is however lacking. Functional expression of H4R on colon epithelial cells is a prerequisite to pursue the hypothesis of involvement of H4R in carcinogenesis. Thus, we here compared the expression of histamine receptor subtypes in a series of cell lines. Out of these, three colon-derived cell lines displaying different combinations of H1R and H4R expression were submitted to functional analyses. Human hematopoietic HMC-1, HL-60, and U937, lung-derived A549 and Calu-3, and colorectal LoVo, SW 480, Caco-2, HT-29, and HCT116 cells were included in the study. mRNA expression was quantified by RT-qPCR. For functional analyses, Caco-2, HT-29, and HCT116 cells were treated by incubation with 1 – 10 µM histamine in the presence or absence of selective histamine receptor antagonists. Calcium mobilization, cAMP accumulation, and cell proliferation were measured by fluorimetry, mass spectrometry, and real-time bioimpedance measurements, respectively. Histamine receptor expression was heterogeneous in the cell lines tested. In most cell lines, we detected H1R mRNA while H4R mRNAs were found only occasionally. The colon-derived epithelial cell lines LoVo, SW480, and HT-29 expressed H1R mRNA exclusively, while in HCT116 cells H1R and H4R mRNAs and in CaCo-2 H2R mRNA were detectable. Subsequent functional analyses in HT29, Caco-2, and HCT116 cells, however, indicated that only HT-29 responded to histamine stimulation, by means of H1R. For a detailed analysis of histamine receptor function, esp. that of H1R and H4R, in human colon-derived cell lines, the cell lines tested here are not fully convenient unless genetically modified.

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Section: Introductionmentioning

confidence: 84%

Histamine H1- and H4-receptor expression in human colon-derived cell lines

Schrammel,

König,

Frommer

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Interestingly, mast cells have been found to be abundant in colon carcinoma and to promote carcinogenesis in chemically-induced CRC in mice [ 120 ], and are associated with a poor prognosis in human CRC patients [ 121 ]. In analogy to the pro-inflammatory effect of histamine via the H4R, the absence of H4R expression also leads to a reduction in chemically-induced carcinogenesis in mice [ 122 ]. However, some indications arise from the observation that the expression of H4R decreases in gastric carcinoma during progression, accompanied by the attenuated histamine-induced suppression of proliferation [ 119 , 123 ].…”

Section: Role Of Histamine In Intestine Disordersmentioning

confidence: 99%

Histamine: A Mediator of Intestinal Disorders—A Review

Smolińska

Winiarska

Głobińska³

et al. 2022

Metabolites

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Within the gastrointestinal tract, histamine is present at relatively high concentrations, especially during inflammatory processes. Histamine is a biogenic amine with numerous effects on many cell types, mediated by the activation of its four different histamine receptors (H1–H4Rs). It is produced and released by immune cells as mast cells and basophils. Some cells such as dendritic cells or T cells can express histidine decarboxylase, an enzyme for histamine synthesis after stimulation. The same can be done by the human gut microbiota. The production of histamine by bacteria in the human gut influence the immune response, although the major source of histamine is food. The large spectrum of histamine effects on a number of cellular processes results in various gastrointestinal disorders including food allergy, histamine intolerance, irritable bowel syndrome, and inflammatory bowel disease, among others. In this review, the protective or pathogenic effects of histamine on various gut disorders are discussed.

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“…Regarding the modes of action of histamine discussed above, the question arises if specific receptor subtypes are responsible for these different effects of histamine on inflammatory cells and tumor-regulating cells. In analogy to the pro-inflammatory effect of histamine via the H 4 R that has already been discussed above, the absence of H 4 R expression also leads to a reduction of chemically-induced carcinogenesis in mice [ 131 ]. Whether this is due to the reduced inflammation promoting carcinogenesis or to an effect of histamine on the tumor cell itself is unknown at present.…”

Section: Histamine and Carcinogenesismentioning

confidence: 99%

The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut

Schirmer

Neumann

2021

IJMS

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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.

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Genetic Deficiency of the Histamine H4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice

Cited by 8 publications

References 51 publications

Histamine H1- and H4-receptor expression in human colon-derived cell lines

Histamine H1- and H4-receptor expression in human colon-derived cell lines

Histamine: A Mediator of Intestinal Disorders—A Review

The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut

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