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The Chemotherapeutic Agent, 5,6-Dimethylxanthenone-4-Acetic Acid,

ABSTRACT: Vascular disrupting agents (VDA) represent a novel approach to the treatment of cancer, resulting in 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. The data presented herein demonstrate that DMXAA is a novel and specific activator of the TBK1-IRF-3 signaling pathway. DMXAA treatment of primary murine macrophages resulted in robust IRF-3 activation, a ~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 NF-kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3, but MyD88-, TRIF-, IPS-1/MAVS-, and IKKbeta-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of murine 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 (SA). These findings detail a novel pathway for TBK-1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs. Keywords: DMXAA, IRF-3, TBK1, IFN-beta, Salicylic acid, TLR

ORGANISM(S): Mus musculus

PROVIDER: GSE7194 | GEO | 2007/03/08

SECONDARY ACCESSION(S): PRJNA98237

REPOSITORIES: GEO

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Project description:We investigated the roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3-/-7-/- mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 hours after infection; however, they remained resistant to lethal infection. IFN-α/β was induced similarly in wild-type and Irf-3-/- mice post DENV infection, whereas in the Irf-7-/- and Irf-3-/-7-/- mice, significantly low levels of IFN-α/β expression was observed within 24 hours post-infection. IFN-stimulated gene (ISG) induction was also delayed in Irf-3-/-7-/- mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3-/-7-/- mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3-/-7-/- mice 24 hours after infection, at which time point viral titers peaked and started to be cleared. Antibody-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3-/-7-/- mice. Additionally, the ISGs Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/β response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity. To identify the antiviral genes that are controlled by IRF-3 and IRF-7 signaling during DENV infection, we examined a panel of ISG expression in the spleens of wild-type, Irf-3-/-, Irf-7-/- and Irf-3-/-7-/- mice at 12 or 24 hours after DENV infection using a quantitative PCR array kit. The fold changes in expression of 55 genes from infected mice were normalized to that of strain-matched naïve mice.

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The Chemotherapeutic Agent, 5,6-Dimethylxanthenone-4-Acetic Acid,

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