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J Allergy Clin Immunol. 2009 Mar;123(3):619-25. doi: 10.1016/j.jaci.2008.12.1110.

The histamine H4 receptor is functionally expressed on T(H)2 cells.

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Department of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany.



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.


To investigate expression, regulation, and function of the H(4)R on human CD4(+) T cells.


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.


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.


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.

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