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PMID: 17562815 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis.

The Journal of experimental medicine ·Vol. 204 ·No. 7 ·2007-07-09 ·Pages 1559-69

Roberts ZJ, Goutagny N, Perera PY, Kato H, Kumar H, Kawai T, Akira S, Savan R, van Echo D, Fitzgerald KA, Young HA, Ching LM, Vogel SN

Abstract

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.

MeSH Terms
Animals Antineoplastic Agents/therapeutic use Cells, Cultured Cytokines/analysis DNA/genetics Enhancer Elements, Genetic Female Gene Expression Regulation/drug effects Immunoglobulin Light Chains/genetics Interferon Regulatory Factor-3/metabolism Macrophages, Peritoneal/drug effects,physiology Mice Mice, Inbred C57BL Polymerase Chain Reaction Protein Kinases/metabolism Protein Serine-Threonine Kinases/metabolism Signal Transduction/drug effects Xanthones/therapeutic use
Chemicals
Antineoplastic Agents Cytokines Immunoglobulin Light Chains Interferon Regulatory Factor-3 Xanthones vadimezan DNA Protein Kinases Tbk1 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Roberts Zachary J
Department of Microbiology and Immunology, University of Maryland-Baltimore, Baltimore, MD 21201, USA.
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
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20061845
Published
2007-07-09
Epub
2007-00-11
Pages
1559-69
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118649
Subset
IM
Grants
NIAID NIH HHS · T32 AI 007540 · United States
NIAID NIH HHS · R01 AI044936 · United States
NIAID NIH HHS · R37 AI067497 · United States
NIAID NIH HHS · R01 AI067497 · United States
NIAID NIH HHS · R56 AI067497 · United States
NIAID NIH HHS · T32 AI007540 · United States
NIAID NIH HHS · R37 AI018797 · United States
NIAID NIH HHS · AI 18797 · United States
NIAID NIH HHS · AI 067497 · United States
NIAID NIH HHS · R01 AI018797 · United States
NIAID NIH HHS · AI 44936 · United States
NIAID NIH HHS · R56 AI018797 · United States
External Links
PubMed source DOI: 10.1084/jem.20061845 PMC Full Text View journal details
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