Triptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha.
Triptolide is a biologically active component purified from Chinese herbal plant Tripterygium wilfordii Hook F. It is widely used in East Asia for treatment of systemic lupus erythematosus, rheumatoid arthritis, nephritis, Bechect's disease, psoriasis, atopic dermatitis, and asthma. However, its immunological mechanisms are poorly understood. IL-12 and IL-23 are closely related heterodimeric cytokines that share the common subunit p40. They are produced by APCs and are key factors in the generation and effector functions of Th1 and Th17 cells, respectively. They have been strongly implicated in the pathogenesis of several autoimmune disorders. In this study, we investigated the molecular mechanism whereby triptolide inhibits the expression of the p40 gene in APCs. We demonstrate that triptolide does so at the transcriptional level in part through targeting CCAAT/enhancer-binding protein-alpha (C/EBPalpha), which directly interacts with the p40 promoter and inhibits its transcription in inflammatory macrophages. Triptolide can activate the transcription of C/EBPalpha, and phosphorylation of Ser21 and Thr222/226 critical for C/EBPalpha inhibition of p40. Further, activation of C/EBPalpha by triptolide is dependent on upstream kinases ERK1/2 and Akt-GSK3beta. This study provides mechanistic insights into the immunomodulatory capacity of triptolide and has strong implications for its therapeutic applications in autoimmune diseases.
Zhang
Yan
Y
Department of Microbiology and Immunology, Weill Medical College, eill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
Ma
Xiaojing
X
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D004852:Epoxy Compounds / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016056:Immunodominant Epitopes / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology; D053759:Interleukin-23 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D010616:Phenanthrenes / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D022763:CCAAT-Enhancer-Binding Protein-alpha; D004224:Diterpenes; D004852:Epoxy Compounds; D016056:Immunodominant Epitopes; D007166:Immunosuppressive Agents; D053759:Interleukin-23; C495942:P40, iodinated C-terminal peptide, human; D010446:Peptide Fragments; D010616:Phenanthrenes; D018664:Interleukin-12; C001899:triptolide