Pimecrolimus induces apoptosis of mast cells in a murine model of cutaneous mastocytosis.
BACKGROUND
Cutaneous mastocytosis (CM) is a common type of mastocytosis. Current treatment of CM is generally symptomatic. Pimecrolimus has been demonstrated as an effective anti-inflammatory drug for the treatment of inflammatory skin diseases, but whether it treats CM remains unknown.


METHODS
The murine model of CM was induced by subcutaneous injection of 100 μg/kg recombinant murine stem cell factor (rmSCF) for a total of 17 days in Balb/c mice. Beginning on the 8th day, treatment with pimecrolimus 1% cream or vehicle was performed topically and daily for 10 days. The clinical signs of CM were scored, and pathological analysis was performed with toluidine blue staining and hematoxylin and eosin staining. The in situ apoptotic mast cells (MCs) were studied by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The cutaneous histamine level was measured by ELISA.


RESULTS
In the rmSCF-treated mice, the clinical signs of CM, including erythema, wheal after rubbing lesion skins, and increased thickness of skin, were obvious compared to control mice, and were reduced after pimecrolimus treatment. The numbers of cutaneous MCs and neutrophils were significantly greater in mice with CM than in control mice, and pimecrolimus treatment decreased the numbers of MCs but not neutrophils. Extensive apoptosis of cutaneous MCs was observed in pimecrolimus-treated mice. The cutaneous histamine level was elevated in the mice with CM compared with healthy controls, and was lowered after treatment with pimecrolimus.


CONCLUSIONS
Pimecrolimus effectively treats CM by reducing the density of cutaneous MCs and the subsequent histamine production through inducing MCs apoptosis.
Ma
Zhongcai
Z
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Torrance, CA 90502, USA. zcma@labiomed.org
Tovar
Jason P
JP
Kwong
Kenny Y C
KY
Paek
David
D
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D004890:Erythema; D006632:Histamine / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007279:Injections, Subcutaneous; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034701:Mastocytosis, Cutaneous / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D019089:Stem Cell Factor / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019089:Stem Cell Factor; C117268:pimecrolimus; D006632:Histamine; D016559:Tacrolimus