The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation.
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.
Cowden
Jeffery M
JM
Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121, USA.
Zhang
Mai
M
Dunford
Paul J
PJ
Thurmond
Robin L
RL
D000818:Animals; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D016650:Fluorescein-5-isothiocyanate; D006633:Histamine Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020381:Interleukin-17 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D010879:Piperazines / Q000494:pharmacology; D011537:Pruritus / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D011968:Receptors, Histamine / Q000235:genetics / Q000276:immunology*; D000074040:Receptors, Histamine H4; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; D007211:Indoles; D020381:Interleukin-17; D015848:Interleukin-5; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D015847:Interleukin-4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D016650:Fluorescein-5-isothiocyanate