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¹ Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, MD 21201
² Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605
³ Veterans Administration Medical Center, Washington, DC 20422
⁴ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
⁵ Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Frederick, MD 21702
⁶ Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1000, New Zealand

CORRESPONDENCE Stefanie Vogel: svogel{at}som.umaryland.edu

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 750-fold increase in IFN-ß 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 B–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-ß–, IFN promoter-stimulator 1–, and inhibitor of B 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-ß 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.

Abbreviations used: DMXAA, 5,6-dimethylxanthenone-4-acetic acid; GST, glutathione S transferase; IB, inhibitor of B; IKK, IB kinase; IP-10, IFN-inducible protein 10; IPS-1, IFN-ß promoter-stimulator 1; IRF-3, IFN regulatory factor 3; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; MyD88, myeloid differentiation factor 88; PAMP, pathogen-associated molecular pattern; PRD, positive regulatory domain; RANTES, regulated on activation, normal T expressed and secreted; RIG-I, retinoic acid–inducible gene I; SA, salicylic acid; TBK1, TANK-binding kinase 1; TIR, Toll–IL-1 resistance; TLR, Toll-like receptor; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain–containing adaptor inducing IFN-ß; VDA, vascular disrupting agent.

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