Tumor formation and antitumor immunity; the overlooked significance of histamine

Falus, András; Gilicze, Anna

doi:10.1189/jlb.3ri0413-217rr

Cited by 8 publications

(3 citation statements)

References 69 publications

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“…Histamine is a biogenic amine which is widely distributed and has many functions 4 5 6 7 . Several studies have found that the levels of histamine in the serum and myocardium increased significantly in acute myocardial infarction (AMI) 8 9 10 11 12 .…”

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confidence: 99%

Histamine deficiency exacerbates myocardial injury in acute myocardial infarction through impaired macrophage infiltration and increased cardiomyocyte apoptosis

Deng

Hong

Lin

et al. 2015

Sci Rep

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Histamine is a biogenic amine that is widely distributed and has multiple functions, but the role it plays in acute myocardial infarction (AMI) remains unclear. In this study, we investigated the origin and contribution of endogenous histamine to AMI. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine generation. Using HDC-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the HDC promoter, we identified HDC expression primarily in CD11b+Gr-1+ immature myeloid cells (IMCs) that markedly increase in the early stages of AMI. Deficiency of histamine in HDC knockout mice (HDC−/−) reduced cardiac function and exacerbated the injury of infarcted heart. Furthermore, administering either an H1 receptor antagonist (pyrilamine) or an H2 receptor antagonist (cimetidine) demonstrated a protective effect of histamine against myocardial injury. The results of in vivo and in vitro assays showed that histamine deficiency promotes the apoptosis of cardiomyocytes and inhibits macrophage infiltration. In conclusion, CD11b+Gr-1+ IMCs are the predominant HDC-expressing sites in AMI, and histamine plays a protective role in the process of AMI through inhibition of cardiomyocyte apoptosis and facilitation of macrophage infiltration.

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confidence: 99%

Histamine deficiency exacerbates myocardial injury in acute myocardial infarction through impaired macrophage infiltration and increased cardiomyocyte apoptosis

Deng

Hong

Lin

et al. 2015

Sci Rep

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“…Elevated quantities of histamine have been detected in some malignancies such as breast, prostate, ovarian, cervical-and lung cancer (Kubecova et al, 2011). Various types of malignant cells also express the H2 receptor, and histamine may directly induce the expansion of certain tumor cells and/or exerts pro-tumor activities through H2 receptor-mediated immune suppression (Falus and Gilicze, 2014;Faustino-Rocha et al, 2017;Jafarzadeh et al, 2019). The overexpression of COX-2 and PGE2 was also reported in cancerous cells, which are related to tumor progression and resistance to current therapeutic elements (Pang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Cimetidine and Ibuprofen Modulate T Cell Responses in a Mouse Model of Breast Cancer

Oladpour

Taghipour

Hassan

et al. 2022

Asian Pac J Cancer Prev

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Cimetidine and ibuprofen exhibit immunomodulatory effects as an antagonist of histamine H2 receptor, and a cyclooxygenase inhibitor, respectively. Here, the effects of cimetidine and ibuprofen on some effector T cell-related parameters were investigated using a breast cancer (BC) model. BC was established in Balb/c mice using the 4T1 cell line. On day 10 after tumor induction, the BC-bearing mice were classified into four groups and treated with PBS, cimetidine (20 mg/kg), ibuprofen (20 mg/kg) or a combination of "cimetidine + ibuprofen" via intraperitoneal injection (daily from days 11 to 30). The mice were sacrificed on day 31 and the frequency of splenic Th1 and Treg cells, plasma IFN-γ and TGF-β levels, and intra-tumoral T-bet, GATA3, FOXP3 and RORγt expressions were detected using flowcytometry, ELISA and real-time-PCR, respectively. In untreated cancerous mice, the percentage of splenic Th1 cells and plasma IFN-γ levels were lower (P<0.003 and P<0.01, respectively), whereas the percentage of splenic Treg cells and plasma TGF-β levels were higher than in healthy mice (P<0.04 and P<0.005, respectively). Treatment of BC-bearing mice with cimetidine, ibuprofen or both drugs promoted the frequency of Th1 cells (P<0.05, P<0.007 and P<0.005, respectively) as well as IFN-γ levels (P<0.004, P<0.0001 and P<0.03, respectively), while reduced the frequencies of Treg cells (P<0.02, P<0.03 and P<0.01, respectively), TGF-β levels (P<0.006, P<0.02 and P<0.002, respectively), intra-tumoral expression of FOXP3 (P<0.006, P<0.005 and P<0.005, respectively), and intra-tumoral expression of RORγt (P<0.04, P<0.03 and P<0.05, respectively) compared with untreated BC mice. The "cimetidine + ibuprofen"-treated mice displayed greater T-bet expression than the un-treated mice (P<0.006). Cimetidine and/or ibuprofen-treated BC-bearing mice exhibited reduced intra-tumoral expression of GATA3 compared with the untreated BC mice, but the differences were not significant. Cimetidine and ibuprofen correct some effector T cell-related parameters in cancerous mice. Immunotherapeutic potentials cimetidine and ibuprofen in cancers need investigations.

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“…Histamine is a biogenic amine involved in a variety of physiological and pathophysiological functions in the context of allergic responses, gastric acid secretion, immune modulation, and carcinogenesis4567. Although increases in histamine levels during the early stage of MI have been documented8910, the origin and effects of histamine with respect to the development of heart failure post-MI, as well as the mechanisms underlying these effects, are still controversial.…”

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Aggravated myocardial infarction-induced cardiac remodeling and heart failure in histamine-deficient mice

Chen

Hong

Ding

et al. 2017

Sci Rep

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Histamine has pleiotropic pathophysiological effects, but its role in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Histidine decarboxylase (HDC) is the main enzyme involved in histamine production. Here, we clarified the roles of HDC-expressing cells and histamine in heart failure post-MI using HDC-EGFP transgenic mice and HDC-knockout (HDC−/−) mice. HDC+CD11b+ myeloid cell numbers markedly increased in the injured hearts, and histamine levels were up-regulated in the circulation post-MI. HDC−/− mice exhibited more adverse cardiac remodeling, poorer left ventricular function and higher mortality by increasing cardiac fibrogenesis post-MI. In vitro assays further confirmed that histamine inhibited heart fibroblast proliferation. Furthermore, histamine enhanced the signal transducer and activator of transcription (STAT)-6 phosphorylation level in murine heart fibroblasts, and the inhibitive effects of histamine on fibroblast proliferation could be blocked by JAK3/STAT6 signaling selective antagonist. STAT6-knockout (STAT6−/−) mice had a phenotype similar to that of HDC−/− mice post-MI; however, in contrast to HDC−/− mice, the beneficial effects of exogenous histamine injections were abrogated in STAT6−/− mice. These data suggest that histamine exerts protective effects by modulating cardiac fibrosis and remodeling post-MI, in part through the STAT6-dependent signaling pathway.

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Tumor formation and antitumor immunity; the overlooked significance of histamine

Cited by 8 publications

References 69 publications

Histamine deficiency exacerbates myocardial injury in acute myocardial infarction through impaired macrophage infiltration and increased cardiomyocyte apoptosis

Histamine deficiency exacerbates myocardial injury in acute myocardial infarction through impaired macrophage infiltration and increased cardiomyocyte apoptosis

Cimetidine and Ibuprofen Modulate T Cell Responses in a Mouse Model of Breast Cancer

Aggravated myocardial infarction-induced cardiac remodeling and heart failure in histamine-deficient mice

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