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

2021 ◽  
Vol 22 (11) ◽  
pp. 6116
Author(s):  
Bastian Schirmer ◽  
Detlef Neumann
Keyword(s):  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Histamine H4 Receptor ◽  
Ongoing Research ◽  
Inflammatory Reactions ◽  
Beneficial Effects ◽  
Associated Diseases ◽  
Physiological Processes ◽  
H4 Receptor ◽  
Deficient Mice

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.

Targeting the Histamine H4 Receptor: Future Drugs for Inflammatory Diseases

2018 ◽  
Vol 22 (17) ◽  
pp. 1663-1672 ◽  
Author(s):  
Michelle Fidelis Correa ◽  
Joao Paulo dos Santos Fernandes
Keyword(s):  
Inflammatory Diseases ◽  
Histamine H4 Receptor ◽  
H4 Receptor

Cloning and characterization of dominant negative splice variants of the human histamine H4 receptor

2008 ◽  
Vol 414 (1) ◽  
pp. 121-131 ◽  
Author(s):  
Richard M. van Rijn ◽  
André van Marle ◽  
Paul L. Chazot ◽  
Ellen Langemeijer ◽  
Yongjun Qin ◽  
...  
Keyword(s):  
Mast Cells ◽  
Mammalian Cells ◽  
Splice Variants ◽  
Inflammatory Diseases ◽  
Dominant Negative ◽  
Full Length ◽  
Dominant Negative Effect ◽  
Histamine H4 Receptor ◽  
Negative Effect ◽  
H4 Receptor

The H4R (histamine H4 receptor) is the latest identified member of the histamine receptor subfamily of GPCRs (G-protein-coupled receptors) with potential functional implications in inflammatory diseases and cancer. The H4R is primarily expressed in eosinophils and mast cells and has the highest homology with the H3R. The occurrence of at least twenty different hH3R (human H3R) isoforms led us to investigate the possible existence of H4R splice variants. In the present paper, we report on the cloning of the first two alternatively spliced H4R isoforms from CD34+ cord blood-cell-derived eosinophils and mast cells. These H4R splice variants are localized predominantly intracellularly when expressed recombinantly in mammalian cells. We failed to detect any ligand binding, H4R–ligand induced signalling or constitutive activity for these H4R splice variants. However, when co-expressed with full-length H4R [H4R(390) (H4R isoform of 390 amino acids)], the H4R splice variants have a dominant negative effect on the surface expression of H4R(390). We detected H4R(390)–H4R splice varianthetero-oligomers by employing both biochemical (immunoprecipitation and cell-surface labelling) and biophysical [time-resolved FRET (fluorescence resonance energy transfer)] techniques. mRNAs encoding the H4R splice variants were detected in various cell types and expressed at similar levels to the full-length H4R(390) mRNA in, for example, pre-monocytes. We conclude that the H4R splice variants described here have a dominant negative effect on H4R(390) functionality, as they are able to retain H4R(390) intracellularly and inactivate a population of H4R(390), presumably via hetero-oligomerization.

scholarly journals Histamine H4 receptor regulates IL-6 and INF-γ secretion in native monocytes from healthy subjects and patients with allergic rhinitis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hua Peng ◽  
Jian Wang ◽  
Xiao Yan Ye ◽  
Jie Cheng ◽  
Cheng Zhi Huang ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Allergic Inflammation ◽  
T Cell Subsets ◽  
Histamine H4 Receptor ◽  
Dust Mite ◽  
Monocyte Cell ◽  
Ifn Γ ◽  
H4 Receptor ◽  
Allergen Extracts ◽  
Line Following

Abstract Histamine H1 receptor (H1R) and histamine H4 receptor (H4R) are essential in allergic inflammation. The roles of H4R have been characterized in T cell subsets, whereas the functional properties of H4R in monocytes remain unclear. In the current study, the responses of H4R in peripheral monocytes from patients with allergic rhinitis (AR) were investigated. The results confirmed that H4R has the functional effects of mediating cytokine production (i.e., down-regulating IFN-γ and up-regulating IL-6) in cells from a monocyte cell line following challenge with histamine. We demonstrated that when monocytes from AR patients were stimulated with allergen extracts of house dust mite (HDM), IFN-γ secretion was dependent on H4R activity, but IL-6 secretion was based on H1R activity. Furthermore, a combination of H1R and H4R antagonists was more effective at blocking the inflammatory response in monocytes than treatment with either type of antagonist alone.

scholarly journals The Novel H4R Antagonist 1-[(5-Chloro-2,3-Dihydro-1-Benzofuran-2-Yl)Methyl]-4-Methyl-Piperazine (LINS01007) Attenuates Several Symptoms in Murine Allergic Asthma

2020 ◽  
Vol 54 (6) ◽  
pp. 1163-1176
Keyword(s):  
Lung Tissue ◽  
Inflammatory Diseases ◽  
Lavage Fluid ◽  
Wall Thickening ◽  
Histamine H4 Receptor ◽  
Asthma Model ◽  
Allergic Lung Inflammation ◽  
Inflammatory Processes ◽  
Cox 2 ◽  
H4 Receptor

BACKGROUND/AIMS: Histamine is an important chemical transmitter involved in inflammatory processes, including asthma and other chronic inflammatory diseases. Its inflammatory effects involve mainly the histamine H4 receptor (H4R), whose role in several studies has already been demonstrated. Our group have explored the effects of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines as antagonists of H4R, and herein the compounds LINS01005 and LINS01007 were studied with more details, considering the different affinity profile on H4R and the anti-inflammatory potential of both compounds. METHODS: We carried out a more focused evaluation of the modulatory effects of LINS01005 and LINS01007 in a murine asthma model. The compounds were given i.p. (1-7 mg/kg) to ovalbumin sensitized BALB/c male mice (12 weeks old) 30 min before the antigen challenging, and after 24 h the cell analysis from the bronchoalveolar lavage fluid (BALF) was performed. The lung tissue was used for evaluation by western blot (COX-2, 5-LO, NF-κB and STAT3 expressions) and histological analysis. RESULTS: Treatment with the more potent H4R antagonist LINS01007 significantly decreased the total cell count and eosinophils in BALF at lower doses when compared to LINS01005. The expression of COX-2, 5-LO, NF-κB and STAT3 in lung tissue was significantly reduced after treatment with LINS01007. Morphophysiological changes such as mucus and collagen production and airway wall thickening were significantly reduced after treatment with LINS01007. CONCLUSION: These results show important down regulatory effect of novel H4R antagonist (LINS01007) on allergic lung inflammation.

scholarly journals The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis

2013 ◽  
Vol 73 (3) ◽  
pp. 600-608 ◽  
Author(s):  
Jeffery M Cowden ◽  
Fuqu Yu ◽  
Homayon Banie ◽  
Mandana Farahani ◽  
Ping Ling ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Inflammatory Responses ◽  
Total Production ◽  
Histamine H4 Receptor ◽  
Model Treatment ◽  
H4 Receptor ◽  
The Impact ◽  
Deficient Mice

ObjectiveThe histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models.MethodsH4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood.ResultsBoth H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro.ConclusionsThese results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.

scholarly journals Substrate-specific recognition of IKKs mediated by USP16 facilitates autoimmune inflammation

2021 ◽  
Vol 7 (3) ◽  
pp. eabc4009
Author(s):  
Jian-shuai Yu ◽  
Tao Huang ◽  
Yu Zhang ◽  
Xin-tao Mao ◽  
Ling-jie Huang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Inflammatory Bowel Disease ◽  
Immune Responses ◽  
Bowel Disease ◽  
Theoretical Basis ◽  
Inflammatory Diseases ◽  
Physiological Processes ◽  
Autoimmune Inflammation ◽  
Inflammatory Bowel ◽  
Deficient Mice

The classic NF-κB pathway plays crucial roles in various immune responses and inflammatory diseases. Its key kinase, IKKβ, participates in a variety of pathological and physiological processes by selectively recognizing its downstream substrates, including p105, p65, and IκBα, but the specific mechanisms of these substrates are unclear. Hyperactivation of one of the substrates, p105, is closely related to the onset of inflammatory bowel disease (IBD) in Nfkb1-deficient mice. In this study, we found that IKKβ ubiquitination on lysine-238 was substantially increased during inflammation. Using mass spectrometry, we identified USP16 as an essential regulator of the IKKβ ubiquitination level that selectively affected p105 phosphorylation without directly affecting p65 or IκBα phosphorylation. Furthermore, USP16 was highly expressed in colon macrophages in patients with IBD, and myeloid-conditional USP16-knockout mice exhibited reduced IBD severity. Our study provides a new theoretical basis for IBD pathogenesis and targeted precision intervention therapy.

OCCURRENCE OF THE RISKS FOR DEVELOPMENT OF RESPIRATORY DISEASES IN CHILDREN EXPOSED TO THE CHEMICAL FACTORS OF THE EXPOSURE OF ALUMINA REFINERY- ASSOCIATED BUSINESS ACTIVITY

2019 ◽  
pp. 42-47 ◽  
Author(s):  
M.A. Zemlianova ◽  
I.V. Tikhonova
Keyword(s):  
Respiratory Tract ◽  
Respiratory Diseases ◽  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Respiratory Morbidity ◽  
Upper Respiratory Tract ◽  
Negative Effects ◽  
Wide Range ◽  
Chemical Factors ◽  
Chronic Lymphoproliferative Diseases

Alumina refineries are among the leading sources of atmospheric air pollution with a wide range of pollutants hazardous to human respiratory organs. It is relevant to study and evaluate the occurrence of the risks for development of respiratory diseases in children living in the area affected by the emission components of an alumina refinery. We assessed air quality of the area under observation and comparison according to monitoring observations, risk of non-carcinogenic effects from the respiratory organs. The content of chemicals in the blood and urine adequate to risk factors was quantified. The structure of individual groups of respiratory diseases was analyzed. The causal relationships of violations of laboratory parameters with an increased content of chemicals in biological media were evaluated. It was found that an aerogenic exposure of chemical pollutants is formed on the territory with the production of metallurgical alumina. It determines the risk for development of respiratory diseases, exceeding an acceptable level up to 49.9 times. In the exposed children, the content of manganese, chromium, nickel, copper, xylenes, formaldehyde and aluminum, fluoride ion in the urine was increased to 4.2 times in relation to the indices in the comparison group. A high level of additional respiratory morbidity(1.8 times) was revealed. Chronic lymphoproliferative diseases of the nasopharynx and inflammatory diseases of the upper respiratory tract (up to 6.6 times more often), inflammatory diseases with a predominance of the mechanism of allergic inflammation ( up to 2.1 times more often)are more often detected in the framework of the respiratory diseases. Negative effects on the part of the respiratory system in the form of activation of antioxidant processes, the development of an inflammatory reaction, local, general and specific sensitization of the respiratory tract were established. It confirms the occurrence of the risks for the development of respiratory diseases in children in the exposure area of the chemical factors of alumina refinery-associated economic activity.

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