The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis
Authors
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
Vogel, Stefanie N.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2007-06-15Keywords
AnimalsAntineoplastic 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
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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.Source
J Exp Med. 2007 Jul 9;204(7):1559-69. Epub 2007 Jun 11. Link to article on publisher's siteDOI
10.1084/jem.20061845Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35245PubMed ID
17562815Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1084/jem.20061845