Treatment of Experimental Asthma by Decoy-mediated Local Inhibition of Activator Protein-1

Desmet, Christophe; Gosset, Philippe; Henry, Emmanuelle; Garzé, Virginie; Faísca, Pedro; Vos, Nanda; Jaspar, Fabrice; Mélotte, Dorothée; Lambrecht, Bart; Desmecht, Daniël; Pajak, Bernard; Moser, Muriel; Lekeux, Pierre; Bureau, Fabrice

doi:10.1164/rccm.200410-1431oc

Cited by 42 publications

(34 citation statements)

References 57 publications

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“…Responsiveness to ␤-methacholine (MCh) was assessed in conscious mice using double-chamber whole-body plethysmography (Buxco Europe) and increases in specific airway resistance (sRaw) as an index of airway obstruction (15,16). Baseline measurements were taken and averaged for 3 min after acclimation of the animals to the boxes.…”

Section: Measurement Of Ahrmentioning

confidence: 99%

Dendritic Cells Genetically Engineered to Express IL-10 Induce Long-Lasting Antigen-Specific Tolerance in Experimental Asthma

Henry¹,

Desmet

Garzé³

et al. 2008

The Journal of Immunology

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Section: Measurement Of Ahrmentioning

confidence: 99%

Dendritic Cells Genetically Engineered to Express IL-10 Induce Long-Lasting Antigen-Specific Tolerance in Experimental Asthma

Henry¹,

Desmet

Garzé³

et al. 2008

The Journal of Immunology

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“…7) induced by TNF-α were almost completely inhibited when 0.3 μM BMS-345541 was used. NF-κB and AP-1 are activated in the airways of asthmatic patients and animals (25,26). NF-κB is rapidly activated as a result of the binding with TNFR1, a TNF-α receptor, leading to transcriptional upregulation of adhesion molecules and chemokines (27), because it is likely that NF-κB is the main transcription factor activated by TNF-α in airway smooth muscle (28,29).…”

Section: Involvement Of Nf-κb Activation In the Tnf-α-induced Upregulmentioning

confidence: 99%

Tumor Necrosis Factor–α (TNF-α) Induces Upregulation of RhoA via NF-κB Activation in Cultured Human Bronchial Smooth Muscle Cells

et al. 2009

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Abstract. RhoA plays an important role in Ca 2+ sensitization of bronchial smooth muscle in antigen-induced airway hyperresponsiveness (AHR). Tumor necrosis factor-α (TNF-α), a major proinflammatory cytokine, is capable of inducing AHR, but the mechanisms for this are still unknown. In the present study, the effect of TNF-α on RhoA protein expression was examined in cultured human bronchial smooth muscle cells (hBSMCs). To investigate the role of NF-κB in the TNF-α-induced upregulation of RhoA, the effects of an inhibitor of IκB kinase (IKK), BMS-345541, were also determined. Both immunoblot and immunocytochemical analyses revealed that incubation of the hBSMCs with TNF-α caused an activation of NF-κB (determined by a translocation of p65 proteins to nuclei): the peak response was observed when cells were incubated with 10 ng/mL of TNF-α for 30 min. An upregulation of RhoA protein was also observed at 12 -24 h after the incubation with TNF-α (10 ng/mL). Both the activation of NF-κB and upregulation of RhoA were concentration-dependently inhibited by the co-incubation with BMS-345541. These results suggest that TNF-α-induced upregulation of RhoA might be mediated by an activation of NF-κB in hBSMCs.

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“…Treatment with AP-1 or NF-kB decoy ODN significantly decreased IL-1b, TNF-a, and MPO activities in the tissue contents, which coincided well with the results of our histological examinations (Figure 6a-c). [33][34][35][36][37][38][39][40] Although AP-1 is a major immunoregulatory as well as proinflammatory transcription factor, 21,[27][28][29][30][45][46][47] nothing is known to have been reported regarding the effect of AP-1 inhibition by a decoy ODN on intestinal inflammation. In the present study, we designed a ds decoy ODN binding to AP-1-specific nucleotide sequences and investigated its efficacy to prevent murine experimental DSS-induced colitis.…”

Section: Effects Of Decoy Odns On Expression Of Proinflammatory Cytokmentioning

confidence: 99%

“…33,34 It has been reported that a decoy ODN targeted at the transcription factor nuclear factor (NF)-kB, which plays an essential role in the regulation of a large number of genes involved in immune and inflammatory response, can exert potent immunosuppressive effects with certain inflammatory diseases. [35][36][37] Although the effects of AP-1 decoy ODN have been recently studied in several experimental disease models, [38][39][40] nothing is known regarding its therapeutic potential in gastrointestinal inflammation, including IBD.…”

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confidence: 99%

Decoy oligodeoxynucleotide targeting activator protein-1 (AP-1) attenuates intestinal inflammation in murine experimental colitis

Moriyama

Ishihara

Rumi

et al. 2008

Laboratory Investigation

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Various therapies are used for inflammatory bowel diseases (IBD), though none seem to be extremely effective. AP-1 is a major transcription factor that upregulates genes involved in immune and proinflammatory responses. We investigated decoy oligodeoxynucleotide (ODN) targeting AP-1 to prevent dextran sulfate sodium (DSS)-induced colitis in mice. Functional efficacies of synthetic decoy and scrambled ODNs were evaluated in vitro by a reporter gene luciferase assay and measuring flagellin-induced IL-8 expression by HCT-15 cells transfected with ODNs. Experimental colitis was induced in mice with a 2.5% DSS solution in drinking water for 7 days, and decoy or scrambled ODNs were intraperitoneally injected from days 2 to 5. Colitis was assessed by weight loss, colon length, histopathology, and detection of myeloperoxidase (MPO), IL-1b, and TNF-a in colon tissue. Therapeutic effects of AP-1 and NF-kB decoy ODNs were compared. Transfection of AP-1 decoy ODN inhibited AP-1 transcriptional activity in reporter assays and flagellin-induced IL-8 production in vitro. In mice, AP-1 decoy ODN, but not scrambled ODN, significantly inhibited weight loss, colon shortening, and histological inflammation induced by DSS. Further, AP-1 decoy ODN decreased MPO, IL-1b, and TNF-a in colonic tissue of mice with DSS-induced colitis. The AP-1 decoy therapeutic effect was comparable to that of NF-kB decoy ODN, which also significantly decreased intestinal inflammation. Double-strand decoy ODN targeting AP-1 effectively attenuated intestinal inflammation associated with experimental colitis in mice, indicating the potential of targeting proinflammatory transcription factors in new therapies for IBD.

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Treatment of Experimental Asthma by Decoy-mediated Local Inhibition of Activator Protein-1

Abstract: Our results reveal a key role for AP-1 in the effector phase of pulmonary allergy and indicate that specific AP-1 inhibition in the airways may have therapeutic value in the control of established asthma.

Cited by 42 publications

References 57 publications

Dendritic Cells Genetically Engineered to Express IL-10 Induce Long-Lasting Antigen-Specific Tolerance in Experimental Asthma

Dendritic Cells Genetically Engineered to Express IL-10 Induce Long-Lasting Antigen-Specific Tolerance in Experimental Asthma

Tumor Necrosis Factor–α (TNF-α) Induces Upregulation of RhoA via NF-κB Activation in Cultured Human Bronchial Smooth Muscle Cells

Decoy oligodeoxynucleotide targeting activator protein-1 (AP-1) attenuates intestinal inflammation in murine experimental colitis

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