Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity

Wagner, Andreas H.; Wittjen, Inka; Stojanović, Tomislav; Middel, Peter; Meingassner, Josef G.; Hecker, Markus

doi:10.1016/j.jaci.2007.09.015

Cited by 22 publications

(13 citation statements)

References 37 publications

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“…The present study demonstrated that Art could induce Treg generation and suppress Th17 development. The mechanisms underlying these effects were unclear, but at least some data argued that these occurred dependently of STAT3, which was consistent with the previous investigation of Wagner [37], who used oligodeoxynucleotide to block STAT1 as effectively as STAT3 in CHS animal model. In conclusion, the effects of Art on CHS fulfilled an essential prerequisite for an anti-inflammatory and immune-regulatory candidate, which mechanisms might involve in suppressing Th17 development and inducing Treg generation, correlated with a decrease in the infiltration and the inhibition of inflammatory mediators, and ultimately, the attenuation of the swelling response.…”

Section: Discussionsupporting

confidence: 82%

Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity

Chen

Wei

et al. 2012

International Immunopharmacology

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Section: Discussionsupporting

confidence: 82%

Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity

Chen

Wei

et al. 2012

International Immunopharmacology

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“…(42). Recent studies showed that inflammatory responses in the cochlea are mediated through activation of STAT1, which requires the generation of ROS by NOX3 (43).…”

Section: Discussionmentioning

confidence: 99%

TLR3-Triggered Reactive Oxygen Species Contribute to Inflammatory Responses by Activating Signal Transducer and Activator of Transcription-1

Yang

Kim

Lee

et al. 2013

The Journal of Immunology

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Intracellular reactive oxygen species (ROS) are essential secondary messengers in many signaling cascades governing innate immunity and cellular functions. TLR3 signaling is crucially involved in antiviral innate and inflammatory responses; however, the roles of ROS in TLR3 signaling remain largely unknown. In this study, we show that TLR3-induced ROS generation is required for the activation of NF-κB, IFN-regulatory factor 3, and STAT1-mediated innate immune responses in macrophages. TLR3 induction led to a rapid increase in ROS generation and a physical association between components of the NADPH oxidase (NOX) enzyme complex (NOX2 and p47phox) and TLR3 via a Ca2+-c-Src tyrosine kinase–dependent pathway. TLR3-induced ROS generation, NOX2, and p47phox were required for the phosphorylation and nuclear translocation of STAT1 and STAT2. TLR3-induced activation of STAT1 contributed to the generation of inflammatory mediators, which was significantly attenuated in NOX2- and p47phox-deficient macrophages, suggesting a role for ROS-STAT1 in TLR3-mediated innate immune responses. Collectively, these results provide a novel insight into the crucial role that TLR3-ROS signaling plays in innate immune responses by activating STAT1.

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“…In the present study, the suppression of STAT1 by RNA silencing prevented cell death induction by STAT3-decoy ODN, indicating a critical role for STAT1, independent of IFNγ activation, in line with previous observations showing STAT1-dependent IFN-independent cell death [59]; (see also: [61]). However, STAT1 is the major effector of IFNγ, which is antiproliferative or tumoricidal in several cancer cell types [62,63]; although STAT3-decoy ODN has been found to induce tumor cell death in several different cell systems [17,22-24], it can also inhibit STAT1 [17,64]. Despite their opposing biological effects [65], STAT1 and STAT3 form heterodimers whose function is unclear [66].…”

Section: Discussionmentioning

confidence: 99%

A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-κB

et al. 2011

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BackgroundThe transcription factor STAT3 (signal transducer and activator of transcription 3) is frequently activated in tumor cells. Activated STAT3 forms homodimers, or heterodimers with other TFs such as NF-κB, which becomes activated. Cytoplasmic STAT3 dimers are activated by tyrosine phosphorylation; they interact with importins via a nuclear localization signal (NLS) one of which is located within the DNA-binding domain formed by the dimer. In the nucleus, STAT3 regulates target gene expression by binding a consensus sequence within the promoter. STAT3-specific decoy oligonucleotides (STAT3-decoy ODN) that contain this consensus sequence inhibit the transcriptional activity of STAT3, leading to cell death; however, their mechanism of action is unclear.ResultsThe mechanism of action of a STAT3-decoy ODN was analyzed in the colon carcinoma cell line SW 480. These cells' dependence on activated STAT3 was verified by showing that cell death is induced by STAT3-specific siRNAs or Stattic. STAT3-decoy ODN was shown to bind activated STAT3 within the cytoplasm, and to prevent its translocation to the nucleus, as well as that of STAT3-associated NF-κB, but it did not prevent the nuclear transfer of STAT3 with mutations in its DNA-binding domain. The complex formed by STAT3 and the STAT3-decoy ODN did not associate with importin, while STAT3 alone was found to co-immunoprecipitate with importin. Leptomycin B and vanadate both trap STAT3 in the nucleus. They were found here to oppose the cytoplasmic trapping of STAT3 by the STAT3-decoy ODN. Control decoys consisting of either a mutated STAT3-decoy ODN or a NF-κB-specific decoy ODN had no effect on STAT3 nuclear translocation. Finally, blockage of STAT3 nuclear transfer correlated with the induction of SW 480 cell death.ConclusionsThe inhibition of STAT3 by a STAT3-decoy ODN, leading to cell death, involves the entrapment of activated STAT3 dimers in the cytoplasm. A mechanism is suggested whereby this entrapment is due to STAT3-decoy ODN's inhibition of active STAT3/importin interaction. These observations point to the high potential of STAT3-decoy ODN as a reagent and to STAT3 nucleo-cytoplasmic shuttling in tumor cells as a potential target for effective anti-cancer compounds.

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Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity

Cited by 22 publications

References 37 publications

Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity

Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity

TLR3-Triggered Reactive Oxygen Species Contribute to Inflammatory Responses by Activating Signal Transducer and Activator of Transcription-1

A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-κB

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