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EMBO reports 6, 6, 531–537 (2005)
doi:10.1038/sj.embor.7400433
Published online: 20 May 2005
Activation of IKK by thymosin  1 requires the TRAF6 signalling pathway
Ping Zhang1, Justin Chan1, Ana-Maria Dragoi1, Xing Gong2, Stanimir Ivanov1, Zhi-Wei Li3, Tsheng Chuang4, Cynthia Tuthill5, Yinsheng Wan6, Michael Karin7 & Wen-Ming Chu1
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1 Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA
2 Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA
3 Moffitt Cancer Center and Research Institute, SRB-22344, 3011 West Holly Drive, Tampa, Florida 33612, USA
4 Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
5 SciClone Pharmaceuticals, San Mateo, California 94404, USA
6 Department of Biology, Providence College, North Providence, Rhode Island 02918, USA
7 Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
To whom correspondence should be addressed
Wen-Ming Chu Tel: +1 401 863 9786; Fax: +1 401 863 1971; E-mail: wen-ming_chu@brown.edu
Received 23 August 2004; Accepted 20 April 2005; Published online 20 May 2005.
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Abstract
Thymosin 1 (T1) is noted for its immunomodulatory activities and therapeutic potential in treatment of infectious diseases and cancer. However, the molecular mechanism of its effectiveness is not completely understood. Here, we report that T1 induces interleukin (IL)-6 expression through the I B kinase (IKK) and nuclear factor-B (NF-B) pathway. Using IKK -deficient bone-marrow-derived macrophages and mouse embryo fibroblasts (MEFs), we show that IKK is essential for IKK and NF-B activation as well as efficient IL-6 induction. Further analysis using tumour necrosis factor receptor-associated factor 6 (TRAF6)-deficient MEFs shows that TRAF6 is crucial for activation of IKK and induction of IL-6 by T1. Intriguingly, T1 triggers protein kinase C (PKC) / activation, which is TRAF6 dependent and involves IKK. In addition, T1 induces the formation of a signalsome composed of TRAF6, p62 and PKC/ as well as IKK. Thus, our study identifies T1 as a unique activator of the TRAF6 signal pathway and provides a cohesive interpretation of the molecular basis of the therapeutic utility of T1.
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