Title: Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes
Author: Katrin Schaper Dr. Kristine Rossbach Brigitta K¨other Holger Stark Manfred Kietzmann Thomas Werfel Ralf Gutzmer
Abstract
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
Keratinocyte 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 preincubation 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 ; H2R: amthamine; H2R/H4R: 4-
methylhistamine (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 JNJ7777120. 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.
Keywords: TSLP, histamine, histamine 4 receptor, keratinocytes
