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

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


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dermatitis, Atopic / immunology*
  • Dermatitis, Atopic / metabolism
  • Histamine H3 Antagonists / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Interleukins / immunology
  • Interleukins / metabolism*
  • Methylhistamines / pharmacology
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / immunology*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Histamine / immunology*
  • Receptors, Histamine / metabolism
  • Receptors, Histamine H4
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology
  • Transcription Factor AP-1 / drug effects
  • Transcription Factor AP-1 / immunology
  • Transcription Factor AP-1 / metabolism*


  • HRH4 protein, human
  • Histamine H3 Antagonists
  • IL31 protein, human
  • Imidazoles
  • Interleukins
  • Methylhistamines
  • NF-kappa B
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • Transcription Factor AP-1
  • Interleukin-4
  • 4-methylhistamine
  • Thiourea
  • clobenpropit