The histamine H4 receptor is functionally expressed on T(H)2 cells.
BACKGROUND
Histamine influences T-cell reactions via histamine receptors 1 and 2. The histamine receptor 4 (H(4)R) 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 H(4)R on human CD4(+) T cells.


METHODS
Histamine receptor 4 expression was studied by real-time quantitative RT-PCR and by flow cytometry. Effects of H(4)R stimulation on induction of the signal transduction molecules activator protein 1 (AP-1) and nuclear factor-kappaB (NF-kappaB) 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(H)2 cells than T(H)1 cells and naive T-cells. H(4)R agonists (clobenpropit and 4-methylhistamine) induced AP-1 in T(H)2 cells but not in T(H)1 cells. This effect was blocked by the H(4)R antagonist JNJ7777120. H(4)R agonists upregulated IL-31 mRNA in PBMCs and T(H)2 cells, a cytokine that has been associated with T(H)2 cells and the induction of pruritus. IL-31 mRNA induction by H(4)R stimulation was pronounced in PBMCs from patients with atopic dermatitis. Expression of IL-4, IL-5, and IL-13 was not altered by the H(4)R.


CONCLUSIONS
Human CD4(+) T cells express a functional H(4)R. The receptor is upregulated under T(H)2 conditions, and its stimulation leads to induction of AP-1 and IL-31.
Gutzmer
Ralf
R
Department of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany. gutzmer.ralf@mh-hannover.de
Mommert
Susanne
S
Gschwandtner
Maria
M
Zwingmann
Katja
K
Stark
Holger
H
Werfel
Thomas
T
D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000378:metabolism; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008761:Methylhistamines / Q000494:pharmacology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D011968:Receptors, Histamine / Q000276:immunology* / Q000378:metabolism; D000074040:Receptors, Histamine H4; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
C418607:HRH4 protein, human; D054828:Histamine H3 Antagonists; C502187:IL31 protein, human; D007093:Imidazoles; D007378:Interleukins; D008761:Methylhistamines; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D018808:Transcription Factor AP-1; D015847:Interleukin-4; C025566:4-methylhistamine; D013890:Thiourea; C086108:clobenpropit