title: Suppression of T cell activation by hirsutenone, isolated from the bark of Alnus japonica, and its therapeutic advantages for atopic dermatitis.
abstract: The increasing prevalence and severity of atopic dermatitis during recent decades has prompted the development of safe and more highly effective drugs. Although topical corticosteroids have been used for more than 50 years as first line therapy for atopic dermatitis, their potential side effects limits their clinical uses. In light of this, steroid-free topical calcineurin inhibitors were developed and have been used in patients with moderate to severe atopic dermatitis. In the present study, we examined if hirsutenone suppressed the profiles of atopic dermatitis development in vitro via mimicry of calcineurin inhibitor actions in mouse splenocytes and RBL-2H3 mast cells. Our results showed that hirsutenone effectively inhibited T cell activation by blocking dephosphorylation of nuclear factor of activated T cells (NFAT). This inhibition was confirmed by inactivation of mitogen-activated protein kinases (MAPKs), which subsequently inhibited production of cytokine mRNAs (interleukin-2, -4, -5, -13 and interferon-gamma) after T cell receptor stimulation. We also showed that the early T cell activation marker, CD25, was suppressed in the presence of hirsutenone after T cell receptor stimulation with anti-CD3. Moreover, degranulation of mast cells was remarkably suppressed, comparable to that by cyclosporine A. This indicates that hirsutenone may specifically inhibit calcium-activated processes in both T cells and mast cells. Therefore, our results suggest that hirsutenone may be a new topical drug candidate, which probably acts by mimicking calcineurin inhibitor mechanisms.
authors.affiliation: Research Institute of Veterinary Medicine, Chungbuk National University, Republic of Korea.
authors.forename: Seong Soo
authors.initials: SS
authors.lastname: Joo
authors.forename: Sung Geun
authors.initials: SG
authors.lastname: Kim
authors.forename: Sun Eun
authors.initials: SE
authors.lastname: Choi
authors.forename: Yun-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Hee Yong
authors.initials: HY
authors.lastname: Park
authors.forename: Seong Jun
authors.initials: SJ
authors.lastname: Seo
authors.forename: Young Wook
authors.initials: YW
authors.lastname: Choi
authors.forename: Min Won
authors.initials: MW
authors.lastname: Lee
authors.forename: Do Ik
authors.initials: DI
authors.lastname: Lee
mesh_terms: D029661:Alnus / Q000737:chemistry*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D032701:Biomimetics; D017252:CD3 Complex / Q000276:immunology; D065095:Calcineurin Inhibitors; D002396:Catechols / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology*; D036381:Diarylheptanoids / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D024301:Plant Bark / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D000906:Antibodies; D015415:Biomarkers; D017252:CD3 Complex; D065095:Calcineurin Inhibitors; D002396:Catechols; D016207:Cytokines; D036381:Diarylheptanoids; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; C508777:hirsutenone; D048049:Extracellular Signal-Regulated MAP Kinases; D001619:beta-N-Acetylhexosaminidases