PMID- 22685525
OWN - NLM
STAT- MEDLINE
DCOM- 20121018
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 5
DP  - 2012
TI  - Paradoxical effects of rapamycin on experimental house dust mite-induced asthma.
PG  - e33984
LID - 10.1371/journal.pone.0033984 [doi]
LID - e33984
AB  - 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.
FAU - Fredriksson, Karin
AU  - Fredriksson K
AD  - Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, 
      National Institutes of Health, Bethesda, Maryland, USA.
FAU - Fielhaber, Jill A
AU  - Fielhaber JA
FAU - Lam, Jonathan K
AU  - Lam JK
FAU - Yao, Xianglan
AU  - Yao X
FAU - Meyer, Katharine S
AU  - Meyer KS
FAU - Keeran, Karen J
AU  - Keeran KJ
FAU - Zywicke, Gayle J
AU  - Zywicke GJ
FAU - Qu, Xuan
AU  - Qu X
FAU - Yu, Zu-Xi
AU  - Yu ZX
FAU - Moss, Joel
AU  - Moss J
FAU - Kristof, Arnold S
AU  - Kristof AS
FAU - Levine, Stewart J
AU  - Levine SJ
LA  - eng
GR  - R01 CA125436/CA/NCI NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120525
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Asthma/*drug therapy/*etiology/immunology/metabolism
MH  - Bronchoalveolar Lavage Fluid/chemistry
MH  - Female
MH  - Inflammation/drug therapy/etiology/immunology/metabolism
MH  - Lung/drug effects/immunology/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Phosphorylation/drug effects
MH  - Pyroglyphidae/*immunology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/drug effects/genetics
MH  - Sirolimus/*therapeutic use
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
PMC - PMC3368343
COIS- Competing Interests: JM has received royalties from a patent (United States 
      Provisional Patent Application No. 60/528,340 filed 09 Dec 2003) licensed from 
      the National Institutes of Health (NIH) that is related to the topic of this 
      manuscript. ASK has received research support from the LAM Foundation, the 
      Canadian Institutes of Health, and the NIH (R01 CA125436). ASK also has received 
      funding through a NIH Intramural Research Program Contract. ASK has a patent on a 
      topic related to this manuscript (United States Provisional Patent Application 
      No. 60/528,340 filed 09 Dec 2003). SJL has two patents that are unrelated to the 
      topic of this manuscript (United States Patent 7,135,303, Filed February 28, 2001 
      and United States Patent 7,655,752 B2, Filed March 24, 2006). These competing 
      interests do not alter the authors' adherence to all the PLoS ONE policies on 
      sharing data and materials, as detailed online in the PLoS One guide for authors.
EDAT- 2012/06/12 06:00
MHDA- 2012/10/19 06:00
PMCR- 2012/05/25
CRDT- 2012/06/12 06:00
PHST- 2011/01/12 00:00 [received]
PHST- 2012/02/24 00:00 [accepted]
PHST- 2012/06/12 06:00 [entrez]
PHST- 2012/06/12 06:00 [pubmed]
PHST- 2012/10/19 06:00 [medline]
PHST- 2012/05/25 00:00 [pmc-release]
AID - PONE-D-11-01130 [pii]
AID - 10.1371/journal.pone.0033984 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(5):e33984. doi: 10.1371/journal.pone.0033984. Epub 2012 May 25.