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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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Related in: MedlinePlus

Paradoxical Effect of Rapamycin on Goblet Cell Hyperplasia in House Dust Mite-induced Asthma.Quantification of lung mRNA levels for Muc5AC and Clca3 by qRT-PCR are presented as relative mRNA expression. Results for the induction experiment are shown in Panel A (n = 6 animals per group, * P<0.01), while the results for the treatment experiment are shown in Panel B (n = 5–6 animals per group, P = NS). Results are representative of 2 independent experiments. Goblet cell hyperplasia is presented as the percentage of airways containing PAS-positive cells (n = 8–10 animals per group, * P<0.001). 35.3±0.6 airways were inspected in each mouse.
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pone-0033984-g007: Paradoxical Effect of Rapamycin on Goblet Cell Hyperplasia in House Dust Mite-induced Asthma.Quantification of lung mRNA levels for Muc5AC and Clca3 by qRT-PCR are presented as relative mRNA expression. Results for the induction experiment are shown in Panel A (n = 6 animals per group, * P<0.01), while the results for the treatment experiment are shown in Panel B (n = 5–6 animals per group, P = NS). Results are representative of 2 independent experiments. Goblet cell hyperplasia is presented as the percentage of airways containing PAS-positive cells (n = 8–10 animals per group, * P<0.001). 35.3±0.6 airways were inspected in each mouse.

Mentions: In the induction model, rapamycin administration was associated with small, but significant, decreases in the number of airways demonstrating goblet cell hyperplasia and Clca3 (chloride channel calcium activated 3) mRNA levels, whereas mRNA levels for Muc5AC (mucin 5, subtypes A and C) were not modified (Figure 7). In contrast, rapamycin did not modify goblet cell hyperplasia or mRNA levels of Muc5AC or Clca3 in the treatment model.


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 Goblet Cell Hyperplasia in House Dust Mite-induced Asthma.Quantification of lung mRNA levels for Muc5AC and Clca3 by qRT-PCR are presented as relative mRNA expression. Results for the induction experiment are shown in Panel A (n = 6 animals per group, * P<0.01), while the results for the treatment experiment are shown in Panel B (n = 5–6 animals per group, P = NS). Results are representative of 2 independent experiments. Goblet cell hyperplasia is presented as the percentage of airways containing PAS-positive cells (n = 8–10 animals per group, * P<0.001). 35.3±0.6 airways were inspected in each mouse.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0033984-g007: Paradoxical Effect of Rapamycin on Goblet Cell Hyperplasia in House Dust Mite-induced Asthma.Quantification of lung mRNA levels for Muc5AC and Clca3 by qRT-PCR are presented as relative mRNA expression. Results for the induction experiment are shown in Panel A (n = 6 animals per group, * P<0.01), while the results for the treatment experiment are shown in Panel B (n = 5–6 animals per group, P = NS). Results are representative of 2 independent experiments. Goblet cell hyperplasia is presented as the percentage of airways containing PAS-positive cells (n = 8–10 animals per group, * P<0.001). 35.3±0.6 airways were inspected in each mouse.
Mentions: In the induction model, rapamycin administration was associated with small, but significant, decreases in the number of airways demonstrating goblet cell hyperplasia and Clca3 (chloride channel calcium activated 3) mRNA levels, whereas mRNA levels for Muc5AC (mucin 5, subtypes A and C) were not modified (Figure 7). In contrast, rapamycin did not modify goblet cell hyperplasia or mRNA levels of Muc5AC or Clca3 in the treatment model.

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