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Paradoxical effects of rapamycin on experimental house dust mite-induced asthma.

Fredriksson K, Fielhaber JA, Lam JK, Yao X, Meyer KS, Keeran KJ, Zywicke GJ, Qu X, Yu ZX, Moss J, Kristof AS, Levine SJ - PLoS ONE (2012)

Bottom Line: Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin.We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma.Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT
The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.

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Paradoxical Effect of Rapamycin on Plasma Immunoglobulin Levels in House Dust Mite-induced Asthma.Plasma levels of IgE, IgG1 and IgG2a were quantified. Results for the induction experiment are shown in Panels A, C and E, while results for the treatment experiment are shown in Panels B, D and F (n = 8–20 animals per group, * P<0.05 vs. Saline+Vehicle, ** P<0.001).
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pone-0033984-g006: Paradoxical Effect of Rapamycin on Plasma Immunoglobulin Levels in House Dust Mite-induced Asthma.Plasma levels of IgE, IgG1 and IgG2a were quantified. Results for the induction experiment are shown in Panels A, C and E, while results for the treatment experiment are shown in Panels B, D and F (n = 8–20 animals per group, * P<0.05 vs. Saline+Vehicle, ** P<0.001).

Mentions: Experiments were performed to assess whether rapamycin also has paradoxical effects on plasma IgE production. As shown in Figure 6, administration of rapamycin prior to the induction of HDM-induced asthma markedly attenuated plasma IgE, IgG1 and IgG2a levels, whereas treatment of established airway disease with rapamycin did not significantly modify plasma levels of IgE, IgG1 or IgG2a. These results suggest that inhibition of mTOR signaling with rapamycin inhibited sensitization to HDM allergens in the induction model, but did not reduce production of IgE, IgG1 or IgG2a once HDM sensitization had already occurred.


Paradoxical effects of rapamycin on experimental house dust mite-induced asthma.

Fredriksson K, Fielhaber JA, Lam JK, Yao X, Meyer KS, Keeran KJ, Zywicke GJ, Qu X, Yu ZX, Moss J, Kristof AS, Levine SJ - PLoS ONE (2012)

Paradoxical Effect of Rapamycin on Plasma Immunoglobulin Levels in House Dust Mite-induced Asthma.Plasma levels of IgE, IgG1 and IgG2a were quantified. Results for the induction experiment are shown in Panels A, C and E, while results for the treatment experiment are shown in Panels B, D and F (n = 8–20 animals per group, * P<0.05 vs. Saline+Vehicle, ** P<0.001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368343&req=5

pone-0033984-g006: Paradoxical Effect of Rapamycin on Plasma Immunoglobulin Levels in House Dust Mite-induced Asthma.Plasma levels of IgE, IgG1 and IgG2a were quantified. Results for the induction experiment are shown in Panels A, C and E, while results for the treatment experiment are shown in Panels B, D and F (n = 8–20 animals per group, * P<0.05 vs. Saline+Vehicle, ** P<0.001).
Mentions: Experiments were performed to assess whether rapamycin also has paradoxical effects on plasma IgE production. As shown in Figure 6, administration of rapamycin prior to the induction of HDM-induced asthma markedly attenuated plasma IgE, IgG1 and IgG2a levels, whereas treatment of established airway disease with rapamycin did not significantly modify plasma levels of IgE, IgG1 or IgG2a. These results suggest that inhibition of mTOR signaling with rapamycin inhibited sensitization to HDM allergens in the induction model, but did not reduce production of IgE, IgG1 or IgG2a once HDM sensitization had already occurred.

Bottom Line: Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin.We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma.Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT
The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.

Show MeSH
Related in: MedlinePlus