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Results: 7

1.
Figure 4

Figure 4. From: Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

A trans-dominant negative AhR ablates CYP1A1 induction in MonoMac1 cells. (A) Ectopic overexpression of a truncated AhR (AhR515) in MonoMac1 cells. A Western blot analysis is shown. At the left, the position of molecular weight standards is indicated. (B) AhR515 acts as in a trans-dominant negative fashion by blocking the induction of CYP1A1 expression by VAF347. vector indicates cells infected with the parental retroviral vector.

B. Paige Lawrence, et al. Blood. 2008 August 15;112(4):1158-1165.
2.
Figure 6

Figure 6. From: Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

VAF347 has no biologic effects in MM1 cells expressing reduced AhR levels. The graph shows CYP1A1 (top panel) or IL-6 (middle panel) RNA expression in cells infected with a control shRNA (sh-ctrl) or a sh-AhR retroviral construct. At the bottom, an immunoblot is shown demonstrating reduced AhR protein expression in sh-AhR–infected cells. The size of molecular weight protein standards is given in kilodaltons.

B. Paige Lawrence, et al. Blood. 2008 August 15;112(4):1158-1165.
3.
Figure 7

Figure 7. From: Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

Loss of anti-inflammatory potency of VAG539 in AhR-deficient mice. Allergic lung inflammation was induced in wild-type or AhR−/− mice in the absence or presence of VAG539 treatment and serum IgE levels (top), eosinophilia (middle), and IL-5 (bottom) in the bronchoalveolar fluid were measured. sem indicates standard error of the mean (*P < .05. **P < .01).

B. Paige Lawrence, et al. Blood. 2008 August 15;112(4):1158-1165.
4.
Figure 3

Figure 3. From: Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

VAF347 inhibits cytokine induced IL-6 production in MonoMac1 cells. Top row: induction of CYP1A1 mRNA expression measured by qRT-PCR on treatment with VAF347 and TCDD in the absence or presence of IL-4 and GM-CSF; bottom row: inhibition of IL-4 plus GM-CSF–induced IL-6 transcription by the 2 AhR agonists. The expression levels of CYP1A1 and IL-6 relative to the housekeeping gene eF-1α are depicted. Error bars represent SD.

B. Paige Lawrence, et al. Blood. 2008 August 15;112(4):1158-1165.
5.
Figure 5

Figure 5. From: Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

A trans-dominant negative AhR protein blocks the function of VAF347 in MM1 cells. Loss of biologic activity of VAF347 and TCDD to block IL-6 synthesis in AhR515 overexpressing MonoMac1 cells. Top row: qRT-PCR of IL-4+GM-CSF–induced IL-6 RNA after 24 hours in control (vector) or AhR515-expressing cells; middle row: IL-6 protein was measured in the supernatants from the same cells; bottom row: similar effects as for VAF347 are shown with TCDD on IL-6 mRNA. Error bars represent SD.

B. Paige Lawrence, et al. Blood. 2008 August 15;112(4):1158-1165.
6.
Figure 1

Figure 1. From: Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

Binding to and activation of the AhR by VAF347. (A) Guinea pig hepatic cytosol (2 mg/mL) was incubated with 2 nM of [3H]TCDD in the absence or presence of 100-fold excess TCDF or increasing concentrations of VAF347 or VAG005 for 2 hours at room temperature. [3H]TCDD specific binding was determined using the hydroxyapatite binding assay, as described in “Methods.” Data are presented as a mean plus or minus SD percentage displacement of [3H]TCDD specific binding from at least triplicate incubations. (B) Guinea pig hepatic cystosol (8 mg/mL in HEDG) was incubated with DMSO (2.0%), TCDD (20 nM), or VAF347 (200 nM) for 2 hours at room temperature. Aliquots of each reaction were incubated with [32P]XRE and run by electrophoretic mobility shift analysis to resolve protein-DNA complexes. The arrow indicates the position of the induced ligand/AhR/ARNT/XRE complex and the free (unbound) XRE probe.

B. Paige Lawrence, et al. Blood. 2008 August 15;112(4):1158-1165.
7.
Figure 2

Figure 2. From: Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

VAF347 induces AhR signaling. (A) VAF347 and TCDD, but not VAG005, induce the expression of CYP1A1 mRNA in peripheral blood monocytes. RNA was analyzed by qRT-PCR after a 4-hour incubation period with the compounds alone or in the additional presence of IL-4 and GM-CSF. The expression level of CYP1A1 relative to the housekeeping gene eF-1α is shown. The error bars indicate SD. P values indicate statistical significance determined by a paired Student t test. (B) VAF347 and TCDD, but not VAG005, inhibit IL-6 production by maturing DCs. Monocyte-derived DCs were activated with a cocktail containing GM-CSF, IFN-γ, TNF-α, anti-CD40 mAb, and goat anti–mouse IgG to crosslink the anti-CD40 mAb. The levels of IL-6 were measured in the supernatants by ELISA. (C) VAF347 and TCDD, but not VAG005, inhibit DC-mediated T-cell proliferation. Immature monocyte-derived DCs were pulsed with KLH and subsequently cocultured with autologous CD4+ T cells. The primed T cells were restimulated for 4 additional days with fresh antigen-pulsed DC before T-cell proliferation was measured by tritiated thymidine incorporation.

B. Paige Lawrence, et al. Blood. 2008 August 15;112(4):1158-1165.

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