Dataset Information

Stimulation of histamine H₄ receptors increases the production of IL-9 in Th9 polarized cells.

ABSTRACT:

Background and purpose

Th9 cells represent a recently defined subset of CD4⁺ T-helper cells, characterized by a high production of IL-9. They are found at increased frequency in lesions of atopic dermatitis, where IL-9 is also elevated. As histamine is up-regulated in lesions of inflammatory skin diseases, we investigated the expression profile of histamine receptors and their functional role on Th9 cells.

Experimental approach

Naïve CD4⁺ T-cells were purified from human peripheral blood mononuclear cells, using magnetic beads and further differentiated into Th9 cells. During differentiation, cells were additionally stimulated with histamine receptor agonists or left untreated. Histamine receptor expression as well as IL-9 production was measured.

Key results

As proof of a successful differentiation, IL-9 production was measured at mRNA and protein level. Expression of mRNA for histamine H₁ , H₂ and H₄ receptors were up-regulated in differentiated Th9 cells compared to Th0 cells, while no mRNA for the H₃ receptor was detectable. Stimulation of Th9 cells with histamine significantly up-regulated expression of mRNA and protein for IL-9 . Experiments with specific histamine receptor agonists and antagonists revealed that this up-regulation was mediated by H₄ receptors.

Conclusions and implications

In summary, our study demonstrates a functional role for histamine H₄ receptors on Th9 cells, which might amplify the pro-inflammatory potency of these cells. Together with earlier studies on Th2 and Th17 cells, this study underlines the promising approach for the use of H₄ receptor antagonists in inflammatory and allergic diseases such as atopic dermatitis.

Linked articles

This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

SUBMITTER: Schaper-Gerhardt K

PROVIDER: S-EPMC7012944 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Stimulation of histamine H<sub>4</sub> receptors increases the production of IL-9 in Th9 polarized cells.

Schaper-Gerhardt Katrin K Wohlert Mareike M Mommert Susanne S Kietzmann Manfred M Werfel Thomas T Gutzmer Ralf R

British journal of pharmacology 20190221 3

<h4>Background and purpose</h4>Th9 cells represent a recently defined subset of CD4<sup>+</sup> T-helper cells, characterized by a high production of IL-9. They are found at increased frequency in lesions of atopic dermatitis, where IL-9 is also elevated. As histamine is up-regulated in lesions of inflammatory skin diseases, we investigated the expression profile of histamine receptors and their functional role on Th9 cells.<h4>Experimental approach</h4>Naïve CD4<sup>+</sup> T-cells were purifie ...[more]

PMID: 30589077

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Project description:Histamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H2-histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H2-histamine receptors in a cardiac-specific way (H2-TG) in comparison with their wild-type (WT) littermate controls. We had shown before that histamine exerted concentration and time-dependent positive inotropic and positive chronotropic effects only in cardiac preparations from H2-TG and not from WT. We noted under basal conditions (no drug addition) that right atrial preparations from H2-TG exhibited more spontaneous arrhythmias than right atrial preparations from WT. These arrhythmias in H2-TG could be blocked by the H2-histamine receptor antagonist cimetidine. In a similar fashion, histamine and dimaprit (an agonist at H2 and not H1-histamine receptors) more often induced arrhythmias in right atrial preparations from H2-TG than from WT. To understand better the signal transduction mechanism(s) involved in these arrhythmias, we studied partially depolarized left atrial preparations. In these preparations, a positive inotropic effect of histamine was still present in the additional presence of 44 mM potassium ions (used to block sodium channels) in H2-TG but not WT and this positive inotropic effect could be blocked by cimetidine and this is consistent with the involvement of calcium ion channels in the contractile and thus might mediate also the arrhythmogenic effects of histamine in H2-TG. However, compounds reported to release histamine from cells and thereby leading to arrhythmias in humans, namely morphine, ketamine, and fentanyl, failed to induce a more pronounced positive inotropic effect in atrial preparations from H2-TG compared to WT, arguing against an involvement of histamine release in their proarrhythmic side effects in patients. Measuring left ventricular contractility in isolated retrogradely perfused hearts (Langendorff mode), we detected under basal conditions (no drug application) more spontaneous arrhythmias in hearts from H2-TG than from WT. In summary, we noted that overexpression of human H2-histamine receptors in a novel transgenic animal model can lead to arrhythmias. We suggest that this model might be useful to understand the mechanism(s) of histamine-induced cardiac arrhythmias in humans better in a molecular way and may be of value to screen novel antiarrhythmic drugs.

Project description:The histamine H2 receptor is a member of the family of G-protein-coupled receptors and is linked to the activation of adenylate cyclase phospholipase C (PLC). In this study we examined the effects of protein kinase C (PKC) activation in Chinese hamster ovary (CHO) cells stably expressing canine histamine H2 receptors. Pretreatment with 100 nM phorbol 12-myristate 13-acetate at 37 degrees C for 15 min led to significant potentiation of histamine-dependent and forskolin-dependent cAMP production, whereas the biologically inactive phorbol ester, 4 alpha-phorbol 12, 13-didecanoate, was without effect. These potentiating effects were abolished by preincubation with 0.5 microM bisindolylmaleimide, a PKC inhibitor. Thus the activation of PKCs seems to be involved in the potentiation of cAMP production by acting on a post-receptor mechanism. Preincubation of a CHO cell line, CHO-H2R, with 10 microM histamine for 30 min had two effects. Maximal histamine-dependent cAMP production and forskolin-dependent cAMP production were potentiated by 36% and 105.2% respectively. The other effect was a desensitization of the histamine-dependent adenylate cyclase response as demonstrated by a three-fold increase in EC50. Administration of 0.5 microM bisindolylmaleimide before preincubation of CHO-H2R with 10 microM histamine did not alter the desensitizing effect on cAMP production, but did abolish the sensitizing effect. Preincubation of CHO-H2R cells with 10 nM histamine resulted in moderate potentiation, which was also abolished by bisindolylmaleimide, but not in desensitization of the histamine-dependent cAMP production. Thus these results suggest that preincubation with histamine had a sensitizing effect on cAMP production mediated by PLC and PKC activation, as well as a desensitizing effect on the H2 receptor. The former effect is dependent on the intensity of PLC and PKC signals delivered by H2 receptors. The latter effect requires a higher concentration of histamine.

Dataset Information

Stimulation of histamine H₄ receptors increases the production of IL-9 in Th9 polarized cells.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Linked articles

Publications

Stimulation of histamine H<sub>4</sub> receptors increases the production of IL-9 in Th9 polarized cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Stimulation of histamine H4 receptors increases the production of IL-9 in Th9 polarized cells.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Linked articles

Publications

Stimulation of histamine H<sub>4</sub> receptors increases the production of IL-9 in Th9 polarized cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Stimulation of histamine H₄ receptors increases the production of IL-9 in Th9 polarized cells.