Research Article| Volume 53, ISSUE 3, P216-221, March 2009

Skin application of ketoprofen systemically suppresses contact hypersensitivity by inducing CD4+ CD25+ regulatory T cells



      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).


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


      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.


      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.


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Dermatological Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wakenm P.
        • Gaspari A.A.
        Mechanism of allergic and irritant contact deramtitis.
        in: Kydonieus A.F. Wille J.J. Biochemical modulation of skin reactions transdermals, topicals, cosmetics. CRC Press LLC, Boca Raton2000: 83-106
        • Bos J.D.
        • Teunissen M.B.
        • Kapsenberg M.L.
        Immunology of contact dermatitis.
        Acta Derm Venereol Suppl (Stockh). 1989; 151: 84-87
        • Atarashi K.
        • Kabashima K.
        • Akiyama K.
        • Tokura Y.
        Skin application of nonsteroidal anti-inflammatory drug ketoprofen downmodulates the antigen-presenting ability of Langerhans cells in mice.
        Br J Dermatol. 2008; 159: 306-313
        • Sakaguchi S.
        • Regulatory
        T cells: key controllers of immunologic self-tolerance.
        Cell. 2000; 101: 455-458
        • Walker L.S.
        • Abbas A.K.
        The enemy within: keeping self-reactive T cells at bay in the periphery.
        Nat Rev Immunol. 2002; 2: 11-19
        • Sakaguchi S.
        Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self.
        Nat Immunol. 2005; 6: 345-352
        • Sakaguchi S.
        Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.
        Annu Rev Immunol. 2004; 22: 531-562
        • Sakaguchi S.
        The origin of Foxp3-expressing CD4+ regulatory T cells: thymus or periphery.
        J Clin Invest. 2003; 112: 1310-1312
        • Lohr J.
        • Knoechel B.
        • Abbas A.K.
        Regulatory T cells in the periphery.
        Immunol Rev. 2006; 212: 149-162
        • Sakaguchi S.
        • Sakaguchi N.
        • Shimizu J.
        • Yamazaki S.
        • Sakihama T.
        • Itoh M.
        • et al.
        Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance.
        Immunol Rev. 2001; 182: 18-32
        • Shevach E.M.
        CD4+ CD25+ suppressor T cells: more questions than answers.
        Nat Rev Immunol. 2002; 2: 389-400
        • Takahashi T.
        • Tagami T.
        • Yamazaki S.
        • Uede T.
        • Shimizu J.
        • Sakaguchi N.
        • et al.
        Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.
        J Exp Med. 2000; 192: 303-310
        • Schwarz A.
        • Beissert S.
        • Grosse-Heitmeyer K.
        • Gunzer M.
        • Bluestone J.A.
        • Grabbe S.
        • et al.
        Evidence for functional relevance of CTLA-4 in ultraviolet-radiation-induced tolerance.
        J Immunol. 2000; 165: 1824-1831
        • Fontenot J.D.
        • Gavin M.A.
        • Rudensky A.Y.
        Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells.
        Nat Immunol. 2003; 4: 330-336
        • Hori S.
        • Nomura T.
        • Sakaguchi S.
        Control of regulatory T cell development by the transcription factor Foxp3.
        Science. 2003; 299: 1057-1061
        • Khattri R.
        • Cox T.
        • Yasayko S.A.
        • Ramsdell F.
        An essential role for Scurfin in CD4+ CD25+ regulatory T cells.
        Nat Immunol. 2003; 4: 337-342
        • Roncarolo M.G.
        • Levings M.K.
        The role of different subsets of T regulatory cells in controlling autoimmunity.
        Curr Opin Immunol. 2000; 12: 676-683
        • Shevach E.M.
        • McHugh R.S.
        • Piccirillo C.A.
        • Thornton A.M.
        Control of T-cell activation by CD4+ CD25+ suppressor T cells.
        Immunol Rev. 2001; 182: 58-67
        • Weiner H.L.
        Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells.
        Immunol Rev. 2001; 182: 207-214
        • Groux H.
        • O’Garra A.
        • Bigler M.
        • Rouleau M.
        • Antonenko S.
        • de Vries J.E.
        • et al.
        A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis.
        Nature. 1997; 389: 737-741
        • Mahnke K.
        • Qian Y.
        • Knop J.
        • Enk A.H.
        Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells.
        Blood. 2003; 101: 4862-4869
        • Grohmann U.
        • Orabona C.
        • Fallarino F.
        • Vacca C.
        • Calcinaro F.
        • Falorni A.
        • et al.
        CTLA-4-Ig regulates tryptophan catabolism in vivo.
        Nat Immunol. 2002; 11: 1097-1101
        • Martin E.
        • O’Sullivan B.
        • Low P.
        • Thomas R.
        Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting IL-10.
        Immunity. 2003; 18: 155-167
        • Buckland M.
        • Jago C.B.
        • Fazekasova H.
        • Scott K.
        • Tan P.H.
        • George A.J.
        • et al.
        Aspirin-treated human DCs upregulate ILT-3 and induce hyporesponsiveness and regulatory activity in responder T cells.
        Am J Transplant. 2006; 6: 2046-2059
        • Buckland M.
        • Jago C.
        • Fazekesova H.
        • George A.
        • Lechler R.
        • Lombardi G.
        Aspirin modified dendritic cells are potent inducers of allo-specific regulatory T-cells.
        Int Immunopharmacol. 2006; 6: 1895-1901
        • Thorstenson K.M.
        • Khoruts A.
        Generation of anergic and potentially immunoregulatory CD25+ CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen.
        J Immunol. 2001; 167: 188-195
        • Zhang X.
        • Izikson L.
        • Liu L.
        • Weiner H.L.
        Activation of CD25+ CD4+ regulatory T cells by oral antigen administration.
        J Immunol. 2001; 167: 4245-4253
        • Kavanagh B.
        • O’Brien S.
        • Lee D.
        • Hou Y.
        • Weinberg V.
        • Rini B.
        • et al.
        CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion.
        Blood. 2008; 112: 1175-1183
        • Burkhart C.
        • Liu G.Y.
        • Anderton S.M.
        • Metzler B.
        • Wraith D.C.
        Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10.
        Int Immunol. 1999; 11: 1625-1634
        • Sundstedt A.
        • Höiden I.
        • Rosendahl A.
        • Kalland T.
        • van Rooijen N.
        • Dohlsten M.
        Immunoregulatory role of IL-10 during superantigen-induced hyporesponsiveness in vivo.
        J Immunol. 1997; 158: 180-186
        • Miller C.
        • Ragheb J.A.
        • Schwartz R.H.
        Anergy and cytokine-mediated suppression as distinct superantigen-induced tolerance mechanisms in vivo.
        J Exp Med. 1999; 190: 53-64
        • Bynoe M.S.
        • Evans J.T.
        • Viret C.
        • Janeway Jr., C.A.
        Epicutaneous immunization with autoantigenic peptides induces T suppressor cells that prevent experimental allergic encephalomyelitis.
        Immunity. 2003; 19: 317-328
        • Chen W.J.
        • Wahl S.M.
        TGF-β1: the missing link in CD4+ CD25+ regulatory T cell-mediated immunosuppression.
        Cytokine Growth Factor Rev. 2003; 14: 85-89
        • Taams L.
        • Vukmanovic-Stejic M.
        • Salmon M.
        • Akbar A.
        Immune regulation by CD4+ CD25+ regulatory T cells: implications for transplantation tolerance.
        Transpl Immunol. 2003; 11: 277-285
        • Jonuleit H.
        • Schmitt E.
        • Kakirman H.
        • Stassen M.
        • Knop J.
        • Enk A.H.
        Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells.
        J Exp Med. 2002; 196: 255-260
      1. Yoshiki R, Kabashima K, Sugita K, Atarashi K, Shimauchi T, Tokura Y. IL-10-Producing Langerhans cells and regulatory T cells are responsible for depressed contact hypersensitivity in grafted skin. J Invest Dermatol 2008; October 9 [Epub ahead of print].

        • Fehervari Z.
        • Sakaguchi S.
        Control of Foxp3+ CD25+ CD4+ regulatory cell activation and function by dendritic cells.
        Int Immunol. 2004; 16: 1769-1780
        • Kabashima K.
        • Sakata D.
        • Nagamachi M.
        • Miyachi Y.
        • Inaba K.
        • Narumiya S.
        Prostaglandin E2-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells.
        Nat Med. 2003; 9: 744-749
        • Luft T.
        • Jefford M.
        • Luetjens P.
        Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostagrandin E2 regulates the migratory capacity of specific DC subsets.
        Blood. 2002; 100: 1362-1372
        • Scandella E.
        • Men Y.
        • Gillessen S.
        Prostagrandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells.
        Blood. 2002; 100: 1354-1361
        • Baratelli F.
        • Lin Y.
        Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells.
        J Immunol. 2005; 175: 1483-1490
        • Sharma S.
        • Yang S.C.
        • Zhu L.
        Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer.
        Cancer Res. 2005; 65: 5211-5220