Topical pimecrolimus and tacrolimus transiently induce neuropeptide release and mast cell degranulation in murine skin.
BACKGROUND
The topical calcineurin inhibitors pimecrolimus and tacrolimus have been demonstrated to be an effective new anti-inflammatory therapy. The only clinically relevant side-effect reported is transient application site burning and stinging itch at the beginning of topical therapy.


OBJECTIVE
In order to understand the underlying mechanism of this effect, we examined whether or not the compounds are able to stimulate neuropeptide release in normal murine skin as well as in a mouse model of experimentally induced irritant contact dermatitis.


METHODS
Balb/c mice were treated with 1% pimecrolimus cream or 0.1% tacrolimus ointment. Untreated and corresponding vehicle-treated mice served as controls. Skin specimens were investigated by light, immunofluorescence and electron microscopy as well as enzyme-linked immunosorbent assay and polymerase chain reaction.


RESULTS
Topical application of pimecrolimus and tacrolimus was followed by an initial release of substance P and calcitonin gene-related peptide from primary afferent nerve fibres in murine skin during the early inflammatory response. The release of the neuropeptides and their binding to mast cells (MCs) led to MC degranulation. Mediators of MCs such as histamine and tryptase may induce pruritus and burning by binding to the corresponding receptors (histamine receptor 1, proteinase-activated receptor 2) on sensory nerve fibres, which explains the initial side-effects during therapy with calcineurin inhibitors.


CONCLUSIONS
It may be speculated that calcineurin inhibitors directly stimulate intracellular signalling pathways or bind to ion channels such as transient receptor potential vanilloid 1 or receptors involved in nociception.
Ständer
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Department of Dermatology and Boltzmann Institute for Immuno- and Cell Biology of the Skin, University of Münster, Von-Esmarch-Strasse 58, Münster, Germany. sonja.staender@uni-muenster.de
Ständer
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Seeliger
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Luger
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TA
Steinhoff
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D000287:Administration, Topical; D000818:Animals; D015550:Cell Degranulation; D003877:Dermatitis, Contact / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009479:Neuropeptides / Q000187:drug effects* / Q000378:metabolism; D009824:Ointments; D012867:Skin / Q000187:drug effects; D013373:Substance P / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D009479:Neuropeptides; D009824:Ointments; D013373:Substance P; C117268:pimecrolimus; D016559:Tacrolimus