IgE-mediated mast cell responses are inhibited by thymol-mediated, activation-induced cell death in skin inflammation.
BACKGROUND
Mast cells play a critical role in inflammatory skin diseases through releasing proinflammatory mediators; however, few therapies directly target these cells. In 1878, the use of topical thymol, a now recognized potent agonist for transient receptor potential channels, was first described to treat eczema and psoriasis.


OBJECTIVE
We sought to determine the mechanisms through which thymol can alter skin inflammation.


METHODS
We examined the effect of topical thymol on IgE-dependent responses using a mast cell-dependent passive cutaneous anaphylaxis (PCA) model, as well as in vitro-cultured mast cells.


RESULTS
Thymol dose-dependently inhibited PCA when administered topically 24 hours before antigen challenge but provoked an ear-swelling response directly on application. This direct effect was associated with local mast cell degranulation and was absent in histamine-deficient mice. However, unlike with PCA responses, there was no late-phase swelling. In vitro thymol directly triggered calcium flux in mast cells through transient receptor potential channel activation, along with degranulation and cytokine transcription. However, no cytokine protein was produced. Instead, thymol induced a significant increase in apoptotic cell death that was seen both in vitro and in vivo.


CONCLUSIONS
We propose that the efficacy of thymol in reducing IgE-dependent responses is through promotion of activation-induced apoptotic cell death of mast cells and that this likely explains the clinical benefits observed in early clinical reports.
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill.
Joshua B
JB
Wechsler
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
Chia-Lin
CL
Hsu
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address: p-bryce@northwestern.edu.
Paul J
PJ
Bryce
D000707:Anaphylaxis / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000276:immunology*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D003872:Dermatitis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006632:Histamine / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D010529:Peritoneal Cavity; D000074025:TRPA1 Cation Channel; D013943:Thymol / Q000008:administration & dosage / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D050051:Transient Receptor Potential Channels / Q000378:metabolism
D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D007073:Immunoglobulin E; D013943:Thymol; D006632:Histamine; D002118:Calcium
Mast cell; calcium; passive cutaneous anaphylaxis; thymol