Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis

Abstract

Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.

Identification of new antiviral agents against Kaposi’s sarcoma-associated herpesvirus (KSHV) by high-throughput drug screening reveals the role of histamine-related signaling in promoting viral lytic reactivation

“…It is also possible downstream signaling by specific histamine receptors functions through different proteins and pathways. For example, a recent study in colorectal cancer cells demonstrated that H2R activation reduced MAPK phosphorylation to suppress their activities [44], which differs from the activating effects of other histamine receptors on MAPK pathways [44,45]. Our findings here demonstrate that the MAPK and PI3K/Akt signaling pathways are involved in the histamine-mediated promotion of KSHV lytic reactivation.…”

Characterization of immune landscape in papillary thyroid cancer reveals distinct tumor immunogenicity and implications for immunotherapy

“…HRH1 is a member of histamine receptor family, and it has been reported that inhibition of HRH1 could not only enhance antitumor therapeutic response in breast cancer, 45 but also suppress colonic tumorigenesis. 46 These evidences indicate that HRH1 may also be a potential target in IRS-high PTC patients.…”

Production of a Human Histamine Receptor for NMR Spectroscopy in Aqueous Solutions

“…Activation of H 1 R elicits physiological processes that include modulation of circadian rhythms [ 4 ], responses to allergens, and proinflammatory cytokine production [ 5 ]. H 1 R stimulation has also been implicated in inflammation-associated tumorigenesis [ 6 ]. H 1 R activation by endogenous histamine is blocked by widely recognized drugs known as antihistamines to prevent or reduce allergic responses.…”