Mechanism of Modulation of Interleukin-12 Production by Triptolide

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DESCRIPTION (provided by applicant): Interleukin-12 (IL-12) is a heterodimeric cytokine composed of the p40 and p35 chains. It is produced by antigen-presenting cells (APC) and is a key factor in the induction of T cell-dependent and independent activation of macrophages, Natural Killer (NK) cells, generation of T helper type 1 (Th1) cells and cytotoxic T lymphocytes (CTL), induction of opsonizing, complement-fixing antibodies, and resistance to intracellular infections, and malignant growth. IL-12 and its relative IL-23, which shares the p40 chain with IL-12 together with its unique chain of p19, have also been strongly implicated in the pathogenesis of several types of autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis, inflammatory bowel disease (IBD), and asthma. Triptolide is a biologically active component purified from Chinese herbal plant Tripterygium wilfordii Hook F. (TWHF). The therapeutic use of TWHF in China as a natural medicine can be traced back several centuries. It is widely used in East Asia for treatment of SLE, RA, nephritis, Bechect's disease, psoriasis, atopic dermatitis, asthma, and very recently in prevention of transplant rejection, with little toxicity. Our own preliminary studies indicate that triptolide is able to strongly inhibit dendritic cell (DC) maturation and function including the synthesis of cytokines such as IL-12 and IL-23. In this project, we will investigate the molecular mechanisms whereby triptolide inhibits the transcription of the p40 gene encoding the shared subunit of IL-12 and IL-23 in APCs. Specifically, we will elucidate the essential transcription factors targeted by triptolide in its inhibition of p40 gene expression, as well as the upstream signaling steps that mediate the inhibition. Understanding these mechanisms at the molecular level will benefit the development of therapeutic modalities using triptolide or its derivatives in the treatment of inflammatory autoimmune disorders.