The cytokine thymic stromal lymphopoietin (TSLP) is involved in the development and the progression of allergic diseases. It is mainly released by epithelial cells at barriers such as skin and gut in response to danger signals. Overexpression of TSLP in keratinocytes (KC) can provoke the development of a type
2 inflammatory response. Additionally, TSLP directly acts on sensory neurons and thereby triggers itch. Since
histamine is also increased in lesions of inflammatory skin diseases, the aim of this study was to investigate possible effects of
histamine as well as different
histamine receptor subtype agonists and
antagonists on TSLP production in KC. We therefore stimulated human KC with
histamine in the presence or absence of the known TSLP-inductor poly I:C and measured TSLP production at protein as well as mRNA level. Histamine alone did not induce TSLP production in human KC, but pre-incubation with
histamine prior to challenge with poly I:C resulted in a significant increase of TSLP production compared to stimulation with poly I:C alone. Experiments with different
histamine receptor agonists (H1R:
2-pyridylethylamine; H
2R: amthamine; H
2R/H4R: 4-methyl
histamine (4MH)) revealed a dominant role for the H4R
receptor, as 4-MH in combination with poly I:C displayed a significant increase of TSLP secretion, while the other agonists did not show any effect. The increase in TSLP production by 4MH was blocked with the H4R antagonist JNJ77771
20. This effect was reproducible also in the murine KC cell line MSC.
Taken together, our study indicates a new role for the H4 receptor in the regulation of TSLP in keratinocytes. Therefore, blocking of the H4R receptor in allergic diseases might be promising to alleviate inflammation and pruritus via TSLP.