Inhibiting AKT phosphorylation employing non-cytotoxic anthraquinones ameliorates TH2 mediated allergic airways disease and rhinovirus exacerbation.
BACKGROUND
Severe asthma is associated with T helper (TH) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.


OBJECTIVE
To determine the anti-inflammatory potential of anthraquinones in-vivo.


METHODS
BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.


RESULTS
Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.


CONCLUSIONS
Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.
Department of Parasitology, Microbiology and Immunology, Institute of Biological Sciences, Federal University of Juiz de Fora, Minas Gerais, Brazil ; Experimental&Translational Respiratory Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia ; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Caio Cesar
CC
de Souza Alves
Adam
A
Collison
Luke
L
Hatchwell
Maximilian
M
Plank
Matthew
M
Morten
Paul S
PS
Foster
Sebastian L
SL
Johnston
Cristiane França
CF
da Costa
Mauro Vieira
MV
de Almeida
Henrique
H
Couto Teixeira
Ana
A
Paula Ferreira
Joerg
J
Mattes
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008942:Mitoxantrone / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012229:Rhinovirus / Q000187:drug effects / Q000502:physiology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000880:Anthraquinones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D007372:Interferons; D008942:Mitoxantrone; D051057:Proto-Oncogene Proteins c-akt