The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Antineoplastic Agents; Cells, Cultured; Cytokines; DNA; Enhancer Elements, Genetic; Female; Gene Expression Regulation; Immunoglobulin Light Chains; Interferon Regulatory Factor-3; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Protein Kinases; Protein-Serine-Threonine Kinases; Signal Transduction; Xanthones
Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in the collapse of tumor vasculature and tumor death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. Our data demonstrate that DMXAA is a novel and specific activator of the TANK-binding kinase 1 (TBK1)-interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and approximately 750-fold increase in IFN-beta mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation factor 88-, Toll-interleukin 1 receptor domain-containing adaptor inducing IFN-beta-, IFN promoter-stimulator 1-, and inhibitor of kappaB kinase-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of mouse macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid. These findings detail a novel pathway for TBK1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs.
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Citation: J Exp Med. 2007 Jul 9;204(7):1559-69. Epub 2007 Jun 11. Link to article on publisher's site
Roberts, Zachary J.; Goutagny, Nadege; Perera, Pin-Yu; Kato, Hiroki; Kumar, Himanshu; Kawai, Taro; Akira, Shizuo; Savan, Ram; van Echo, David; Fitzgerald, Katherine A.; Young, Howard A.; Ching, Lai-Ming; and Vogel, Stefanie N., "The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis" (2007). Infectious Diseases and Immunology Publications and Presentations. 79.