期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 204, 期 7, 页码 1559-1569出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20061845
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资金
- NIAID NIH HHS [R56 AI018797, AI 18797, R37 AI067497, AI 44936, R01 AI018797, AI 067497, T32 AI 007540, R01 AI044936, R01 AI067497, R56 AI067497, R37 AI018797, T32 AI007540] Funding Source: Medline
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 11 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 I (TBK1)-interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and similar to 750-fold increase in IFN-P 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 kappa 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-beta-, IFN promoter-stimulator 1-, and inhibitor of KB 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-P 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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