Skin application of ketoprofen systemically suppresses contact hypersensitivity by inducing CD4(+) CD25(+) regulatory T cells.
BACKGROUND
Ketoprofen (KP) is a widely used nonsteroidal anti-inflammatory drug that inhibits prostaglandin biosynthesis. We have previously shown that topical KP treatment at the sensitizing site inhibits the development of contact hypersensitivity (CHS) to picryl chloride (PCl).


OBJECTIVE
We investigated the mechanism underlying the KP-induced immunosuppression of CHS by application of KP.


METHODS
We analyzed the CHS responses to the non-sensitizing site and subsequent sensitization with PCl, and by transfer of the draining lymph node cells (LNCs) from KP-tolerated mice to recipient mice. Changes in the Foxp3 expression of LNCs from KP-phototreated skin were also examined by real-time PCR.


RESULTS
Topical application of KP to not only the sensitizing but also non-sensitizing site suppressed CHS response. The immunosuppression was transferred with LNCs from mice treated with PCl plus KP, but not from mice treated oxazolone plus KP. In this transfer study, the CD4(+) CD25(+) subset of LNCs exerted the suppressive effect, while CD25(+) cell-depleted LNCs lost the inhibitory ability. CTLA-4 blocking with a specific antibody, but not IL-10 blocking, abrogated the activity of CD4(+) CD25(+) cells. Moreover, Foxp3 mRNA expression was remarkably increased in LNCs from PCl and KP-treated mice.


CONCLUSIONS
The immunosuppression of CHS by topical application of KP is systemic and haptein-specific. Treg cells play an important role in the suppressive effect by KP.
Atarashi
Kenji
K
Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan. Kenji_Atarashi@hisamitsu.co.jp
Mori
Tomoko
T
Yoshiki
Ryutaro
R
Kabashima
Kenji
K
Kuma
Hidekazu
H
Tokura
Yoshiki
Y
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism*; D060908:CTLA-4 Antigen; D003877:Dermatitis, Contact / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006241:Haptens / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007660:Ketoprofen / Q000008:administration & dosage / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D010081:Oxazolone / Q000494:pharmacology; D010853:Picryl Chloride / Q000009:adverse effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006241:Haptens; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D010081:Oxazolone; D007660:Ketoprofen; D015232:Dinoprostone; D010853:Picryl Chloride