Paradoxical effects of rapamycin on experimental house dust mite-induced asthma.
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.
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Karin
K
Fredriksson
Jill A
JA
Fielhaber
Jonathan K
JK
Lam
Xianglan
X
Yao
Katharine S
KS
Meyer
Karen J
KJ
Keeran
Gayle J
GJ
Zywicke
Xuan
X
Qu
Zu-Xi
ZX
Yu
Joel
J
Moss
Arnold S
AS
Kristof
Stewart J
SJ
Levine
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D039981:Pyroglyphidae / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus