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Evaluation of peroxisome proliferator‐activated receptor agonists on interleukin‐5‐induced eosinophil differentiation
Author(s) -
Smith Steven G.,
Hill Mike,
Oliveria JohnPaul,
Watson Brittany M.,
Baatjes Adrian J.,
Dua Benny,
Howie Karen,
Campbell Heather,
Watson Rick M.,
Sehmi Roma,
Gauvreau Gail M.
Publication year - 2014
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12280
Subject(s) - eosinophil , agonist , rosiglitazone , peroxisome proliferator activated receptor , receptor , endocrinology , medicine , chemistry , pharmacology , biology , immunology , asthma
Summary Peroxisome proliferator‐activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin‐5 (IL‐5) ‐induced eosinophil differentiation from haemopoietic progenitor cells. Non‐adherent mononuclear cells or CD34 + cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult ® cultures with IL‐5 (10 ng/ml) and IL‐3 (25 ng/ml) in the presence of 1–1000 n m PPAR α agonist (GW9578), PPAR β / δ agonist (GW501516), PPAR γ agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony‐forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood‐extracted CD34 + cells cultured with IL‐5 or IL‐5 + IL‐3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 n m , P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL‐5‐induced phosphorylation of extracellular signal‐regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro , mediated by attenuation of the extracellular signal‐regulated kinase 1/2 signalling pathway. These findings indicate that the PPAR γ agonist can attenuate tissue eosinophilia by interfering with local differentiative responses.