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Effects of the histamine H 4 receptor antagonist JNJ 7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine) were tested in two models of allergic contact dermatitis. Dermatitis was induced by 2,4-dinitrochlorobenzene and toluene-2,4-diisocyanate, which differ in their Th1-Th2 profile in that way that 2,4-dinitrochlorobenzene is a classical contact allergen with a pronounced Th1-mediated inflammation, while the respiratory chemical allergen toluene-2,4-diisocyanate induces a Th2-dominated inflammation. JNJ 7777120 (15 mg ⁄ kg) administered 2 h and 30 min before and 1 h after challenge did not reduce the hapten-induced ear swelling determined 24 h after challenge. This was confirmed by histological evaluation of the ear skin. A repeated administration of the haptens to the rostral part of the back of sensitized animals resulted in a frequent scratching behaviour. An administration of JNJ 7777120 (15 mg ⁄ kg) 30 min before challenge reduced this hapten-induced scratching significantly. The H 1 receptor antagonist cetirizine also reduced the scratching bouts in sensitized mice. A combination of H 1 and H 4 receptor antagonists resulted in the strongest inhibition of scratching behaviour associated with allergic dermatitis. These results indicate that H 4 receptor antagonism fails to reduce the allergic inflammatory response but strongly inhibits allergeninduced itch. Thus, a combination of H 4 and H 1 receptor antagonism might be a new strategy to treat pruritus related to allergic diseases like atopic dermatitis.

H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.

Our findings show that LC express a functional H(4)R and point towards a possible pathogenic relevance of the H(4)R in inflammatory and allergic diseases.

Atopic dermatitis (AD) and psoriasis are common skin diseases with a high negative impact on patients' quality of life. Both diseases are mediated by a pro‐inflammatory infiltrate consisting of several cell types, such as T‐cells, antigen‐presenting cells and granulocytes and display disturbed keratinocyte differentiation. Given the fact that histamine levels are also highly elevated in inflamed skin, it is likely that histamine plays a relevant role in disease pathology. However, antagonists blocking histamine H1 receptor or H2 receptors are largely ineffective in reducing chronic symptoms in AD and psoriasis. Over the last years, much research has been undertaken to shed light into the mode of action of the most recently discovered histamine H4 receptor. This research has shown that H4 receptor antagonists display antipruritic and anti‐inflammatory effects not only in mouse models but also in first human clinical trials, and therefore, H4 receptors might present a novel therapeutic target. In this review, we summarize the effects of the H4 receptors on different cell types, mouse models and clinical studies in regard to AD and psoriasis respectively. Linked Articles This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc

The H4R modulates inflammation in a chronic allergic dermatitis setting. However, results of this study indicate that it is necessary to block the H4R during ontogeny and development of the allergic inflammation.

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