The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation.

Abstract

The role of histamine H(4) receptor (H(4)R) was investigated in a T-helper type 2 (Th2)-cell-mediated mouse skin inflammation model that mimics several of the features of atopic dermatitis. Treatment with two specific H(4)R antagonists before challenge with FITC led to a significant reduction in ear edema, inflammation, mast cell, and eosinophil infiltration. This was accompanied by a reduction in the levels of several cytokines and chemokines in the ear tissue. Upon ex vivo antigen stimulation of lymph nodes, H(4)R antagonism reduced lymphocyte proliferation and IL-4, IL-5, and IL-17 levels. One explanation for this finding is that lymph nodes from animals dosed with the H(4)R antagonist, JNJ 7777120, contained a lower number of FITC-positive dendritic cells. The effect of H(4)R antagonism on dendritic cell migration in vivo may be an indirect result of the reduction in tissue cytokines and chemokines or a direct effect on chemotaxis. In addition to anti-inflammatory effects, JNJ 7777120 also significantly inhibited the pruritus shown in the model. Therefore, the dual effects of H(4)R antagonists on pruritus and Th2-cell-mediated inflammation point to their therapeutic potential for the treatment of Th2-mediated skin disorders, including atopic dermatitis.

• Authors: Jeffery M Cowden, Mai Zhang, Paul J Dunford, Robin L Thurmond
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 130 Issue 4 Pg. 1023-33 (Apr 2010) ISSN: 1523-1747 [Electronic] United States
• PMID: 19907432 (Publication Type: Journal Article)

Chemical References

• Histamine Antagonists
• Hrh4 protein, mouse
• Indoles
• Interleukin-17
• Interleukin-5
• Piperazines
• Receptors, G-Protein-Coupled
• Receptors, Histamine
• Receptors, Histamine H4
• Interleukin-4
• 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
• Fluorescein-5-isothiocyanate

Topics

• Animals
• Chemotaxis (drug effects, immunology)
• Dendritic Cells (cytology, immunology)
• Dermatitis, Atopic (drug therapy, immunology, physiopathology)
• Disease Models, Animal
• Edema (drug therapy, immunology, physiopathology)
• Eosinophils (drug effects, immunology)
• Fluorescein-5-isothiocyanate
• Histamine Antagonists (pharmacology)
• Indoles (pharmacology)
• Interleukin-17 (metabolism)
• Interleukin-4 (metabolism)
• Interleukin-5 (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Mutant Strains
• Piperazines (pharmacology)
• Pruritus (drug therapy, immunology, physiopathology)
• Receptors, G-Protein-Coupled (antagonists & inhibitors, genetics, immunology)
• Receptors, Histamine (genetics, immunology)
• Receptors, Histamine H4
• Th2 Cells (cytology, immunology, metabolism)