title: Shikonin inhibited mitogen-activated IL-4 and IL-5 production on EL-4 cells through downregulation of GATA-3 and c-Maf induction.
abstract: OBJECTIVE
  To investigate the effects of shikonin on phorbol myristate acetate (PMA) plus cyclic adenosine monophosphate (cAMP)-induced T helper (T(H)) 2 cell cytokine production, and the underlying mechanism.
  
  
  METHODS
  We used activated EL-4 murine T-lymphoma cells, which produce interleukin (IL)-4 and IL-5, but not interferon (IFN)-γ, as T(H)2 cell-like cells and treated them with PMA+cAMP to investigate the effects of shikonin on T(H)2 cytokines, transcriptional factors, and the related mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB signaling pathway.
  
  
  RESULTS
  The data show that shikonin inhibited the PMA+cAMP-induced mRNA and protein expression of IL-4 and IL-5 via the downregulation of GATA-binding protein-3 (GATA-3) and c-musculoaponeurotic fibrosarcoma (Maf) but not T-box expressed in T cells (T-bet). Moreover, shikonin suppressed the phosphorylation of p38, inhibitor of κB (IκB) kinase (IKK)-β and IκB-α, and the subsequent IκB-α degradation induced by PMA+cAMP; however, the PMA+cAMP-induced phosphorylation of extracellular signal-related kinase (ERK), which resulted in minor inhibition and phosphorylation of c-Jun N-terminal kinase (JNK), seemed to be unaffected by shikonin treatment.
  
  
  CONCLUSIONS
  This study suggests that downregulation of GATA-3 and c-Maf via the suppression of p38, IKK-β and IκB-α phosphorylation might contribute to the inhibitory effect of shikonin on mitogen-induced IL-4 and IL-5 production in EL-4T cells. Furthermore, shikonin is a potential drug for treating allergic diseases.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan. leechenchen@mail.cmu.edu.tw
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Lee
authors.forename: Jaw-Jou
authors.initials: JJ
authors.lastname: Kang
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
authors.forename: Chien-Neng
authors.initials: CN
authors.lastname: Wang
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000633:toxicity; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D015848:Interleukin-5 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D008934:Mitogens / Q000502:physiology; D009285:Naphthoquinones / Q000494:pharmacology* / Q000633:toxicity; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D020672:I-kappa B Proteins; D015848:Interleukin-5; C495608:Maf protein, mouse; D008934:Mitogens; D009285:Naphthoquinones; D051257:Proto-Oncogene Proteins c-maf; D015847:Interleukin-4; C016101:shikonin; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases