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5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential

Prantner, Daniel ; Perkins, Darren J. ; Lai, Wendy ; Williams, Mark S. ; Sharma, Shruti ; Fitzgerald, Katherine A. ; Vogel, Stefanie N.

The Journal of biological chemistry, 2012-11, Vol.287 (47), p.39776-39788 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential
Autor: Prantner, Daniel ; Perkins, Darren J. ; Lai, Wendy ; Williams, Mark S. ; Sharma, Shruti ; Fitzgerald, Katherine A. ; Vogel, Stefanie N.
Assuntos: Animals ; Antineoplastic Agents - pharmacology ; Antioxidants ; Cytokines/Interferon ; Enzyme Inhibitors - pharmacology ; Immunity, Innate - drug effects ; Immunity, Innate - genetics ; Immunology ; Inflammation ; Innate Immunity ; Interferon-beta - biosynthesis ; Interferon-beta - genetics ; Interferon-beta - immunology ; Interleukin-6 - genetics ; Interleukin-6 - immunology ; Interleukin-6 - metabolism ; Macrophages ; Macrophages, Peritoneal - cytology ; Macrophages, Peritoneal - immunology ; Macrophages, Peritoneal - metabolism ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - metabolism ; Membrane Potential, Mitochondrial - drug effects ; Membrane Potential, Mitochondrial - genetics ; Membrane Potential, Mitochondrial - immunology ; Membrane Proteins - genetics ; Membrane Proteins - immunology ; Membrane Proteins - metabolism ; Mice ; Mice, Knockout ; Mitochondria ; NADPH Oxidase 2 ; NADPH Oxidases - genetics ; NADPH Oxidases - metabolism ; Onium Compounds - pharmacology ; Oxidants - pharmacology ; Pattern Recognition Receptor ; Reactive Oxygen Species (ROS) ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Signal Transduction - immunology ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - immunology ; Tumor Necrosis Factor-alpha - metabolism ; Up-Regulation - drug effects ; Up-Regulation - genetics ; Up-Regulation - immunology ; Xanthones - pharmacology
É parte de: The Journal of biological chemistry, 2012-11, Vol.287 (47), p.39776-39788
Descrição: The chemotherapeutic agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a potent inducer of type I IFNs and other cytokines. This ability is essential for its chemotherapeutic benefit in a mouse cancer model and suggests that it might also be useful as an antiviral agent. However, the mechanism underlying DMXAA-induced type I IFNs, including the host proteins involved, remains unclear. Recently, it was reported that the antioxidant N-acetylcysteine (NAC) decreased DMXAA-induced TNF-α and IL-6, suggesting that oxidative stress may play a role. The goal of this study was to identify host proteins involved in DMXAA-dependent signaling and determine how antioxidants modulate this response. We found that expression of IFN-β in response to DMXAA in mouse macrophages requires the mitochondrial and endoplasmic reticulum resident protein STING. Addition of the antioxidant diphenylene iodonium (DPI) diminished DMXAA-induced IFN-β, but this decrease was independent of both the NADPH oxidase, Nox2, and de novo generation of reactive oxygen species. Additionally, IFN-β up-regulation by DMXAA was inhibited by agents that target the mitochondrial electron transport chain and, conversely, loss of mitochondrial membrane potential correlated with diminished innate immune signaling in response to DMXAA. Up-regulation of Ifnb1 gene expression mediated by cyclic dinucleotides was also impaired by DPI, whereas up-regulation of Ifnb1 mRNA due to cytosolic double-stranded DNA was not. Although both stimuli signal through STING, cyclic dinucleotides interact directly with STING, suggesting that recognition of DMXAA by STING may also be mediated by direct interaction. Background: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates intracellular signaling through uncharacterized pathways similar to those engaged by bacterial pathogens. Results: Mitochondrial targeting agents and absence of STING impair the response to DMXAA in mouse macrophages. Conclusion: Mitochondrial membrane potential is required for optimal response to DMXAA. Significance: This study illustrates that mitochondrial physiology is pivotal in the host response to DMXAA and possibly bacterial pathogens.
Editor: United States: Elsevier Inc
Idioma: Inglês

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5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential

Prantner, Daniel ; Perkins, Darren J. ; Lai, Wendy ; Williams, Mark S. ; Sharma, Shruti ; Fitzgerald, Katherine A. ; Vogel, Stefanie N.

United States: Elsevier Inc

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