The histamine H4 receptor is functionally expressed on TH2 cells

doi:10.1016/j.jaci.2008.12.1110

Journal of Allergy and Clinical Immunology

Volume 123, Issue 3, March 2009, Pages 619-625

https://doi.org/10.1016/j.jaci.2008.12.1110 Get rights and content

Background

Histamine influences T-cell reactions via histamine receptors 1 and 2. The histamine receptor 4 (H₄R) is the most recently identified histamine receptor and is also expressed on human CD4⁺ T cells; however, its regulation and function are unclear.

Objective

To investigate expression, regulation, and function of the H₄R on human CD4⁺ T cells.

Methods

Histamine receptor 4 expression was studied by real-time quantitative RT-PCR and by flow cytometry. Effects of H₄R stimulation on induction of the signal transduction molecules activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) were determined by electrophoretic mobility shift assay and on cytokine production by RT-PCR and ELISA.

Results

Histamine receptor 4 mRNA and protein were expressed by CD4⁺ T cells and upregulated by IL-4. Its expression was higher on T_H2 cells than T_H1 cells and naive T-cells. H₄R agonists (clobenpropit and 4-methylhistamine) induced AP-1 in T_H2 cells but not in T_H1 cells. This effect was blocked by the H₄R antagonist JNJ7777120. H₄R agonists upregulated IL-31 mRNA in PBMCs and T_H2 cells, a cytokine that has been associated with T_H2 cells and the induction of pruritus. IL-31 mRNA induction by H₄R stimulation was pronounced in PBMCs from patients with atopic dermatitis. Expression of IL-4, IL-5, and IL-13 was not altered by the H₄R.

Conclusion

Human CD4⁺ T cells express a functional H₄R. The receptor is upregulated under T_H2 conditions, and its stimulation leads to induction of AP-1 and IL-31.

Section snippets

T-cell isolation, stimulation, and polarization

Buffy coats were used that were disposed of by the blood bank after thrombocyte preparation from anonymous healthy blood donors. Human PBMCs were separated from the buffy coats by density gradient centrifugation on lymphoprep (Fresenius Kabi Norge AS, Halden, Norway). CD4⁺ T cells or CD45RA⁺CD4⁺ naive T cells were isolated by using magnetic beads (Miltenyi Biotech Inc, Bergisch-Gladbach, Germany). Contaminating cells were evaluated in selected experiments by flow cytometry and included minimal

Expression and regulation of the H₄R in human CD4⁺ T cells

mRNA and protein of H₄R could be detected in isolated CD4⁺ T cells from the peripheral blood by RT-PCR and by flow cytometry, respectively (Fig 1, A and B). IL-4 but not IL-13, IFN-γ, and TNF-α upregulated H₄R mRNA in isolated CD4⁺ T cells (Fig 2, A and B). T_H2-polarized CD4⁺ T cells expressed significantly higher H₄R mRNA levels than T_H1-polarized cells (Fig 2, C). This could also be demonstrated on the protein level by flow cytometry (Fig 3). IL-4–stimulated isolated CD4⁺ T cells upregulated

Discussion

We investigated the expression, regulation, and function of the histamine H₄R on human CD4⁺ T cells, because these cells play an important role in allergic diseases such as atopic dermatitis and are likely to come in contact with histamine at sites of allergic inflammation.

We show here on the mRNA and protein level that the H₄R is expressed on CD4⁺ T cells and upregulated on T_H2 cells or by stimulation of CD4⁺ T cells with the T_H2 cytokine IL-4, suggesting a role of the H₄R in a T_H2 milieu.

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: Supported by grants from the Deutsche Forschungsgemeinschaft (DFG Gu434/5-1).

: Disclosure of potential conflict of interest: R. Gutzmer and T. Werfel have received research support from the Deutsche Forschungsgemeinschaft. H. Stark is the founder of and lead scientist for Warburg Glycomed GmbH, has provided legal consultation or expert witness testimony on the subject of clinical projects on H3 receptor ligands, and is the head of the German Pharmaceutical Society—Hessia. The rest of the authors have declared that they have no conflict of interest.

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Reviews and feature articleThe histamine H4 receptor is functionally expressed on TH2 cells

Background

Objective

Methods

Results

Conclusion

Section snippets

T-cell isolation, stimulation, and polarization

Expression and regulation of the H4R in human CD4+ T cells

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Invest Dermatol

Pathophysiology of pruritus in atopic dermatitis: an overview

Exp Dermatol

Dendritic cell modulation by mast cells controls the Th1/Th2 balance in responding T cells

J Immunol

Increased antigen presentation and T(h)1 polarization in genetically histamine-free mice

Int Immunol

Histamine polarizes human dendritic cells into Th2 cell-promoting effector dendritic cells

J Immunol

Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells

J Immunol

Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization

J Clin Invest

Cloning and characterization of a novel human histamine receptor

J Pharmacol Exp Ther

Reviews and feature article
The histamine H₄ receptor is functionally expressed on T_H2 cells

Expression and regulation of the H₄R in human CD4⁺ T cells