Peroxisome Proliferator–activated Receptors α and γ Down-regulate Allergic Inflammation and Eosinophil Activation

Abstract

Allergic asthma is characterized by airway hyperresponsiveness, eosinophilia, and mucus accumulation and is associated with increased IgE concentrations. We demonstrate here that peroxisome proliferator–activated receptors (PPARs), PPAR-α and PPAR-γ, which have been shown recently to be involved in the regulation of various cell types within the immune system, decrease antigen-induced airway hyperresponsiveness, lung inflammation, eosinophilia, cytokine production, and GATA-3 expression as well as serum levels of antigen-specific IgE in a murine model of human asthma. In addition, we demonstrate that PPAR-α and -γ are expressed in eosinophils and their activation inhibits in vitro chemotaxis and antibody-dependent cellular cytotoxicity. Thus, PPAR-α and -γ (co)agonists might be of therapeutic interest for the regulation of allergic or inflammatory reactions by targeting both regulatory and effector cells involved in the immune response.

Peroxisome proliferator–activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model☆

“…29 A single band was detected at 54 to 57 kd, as previously evidenced on adipose tissue. Lung samples and spleen tissue, which was used as a positive control, were homogenized with an Ultra-turrax in 400 lL of buffer (per right lung) containing 1% NP40, 150 mmol/L NaCl, 50 mmol/L Hepes, 10 mmol/L NaF, 0.5 mmol/L Na 3 VO 4 , 1 mmol/L phenylmethylsulfonyl fluoride, and complete protease inhibitor cocktail (Roche) and centrifuged at 13,000 rpm for 10 minutes.…”

“…Both ciglitazone treatments were equally efficient at reducing AHR to methacholine, as measured on the basis of whole-body plethysmography (Fig 1, A) and antigen-specific IgE production associated with the development of this asthma-like reaction (Fig 1, B), as well as eosinophil numbers in bronchoalveolar lavage fluid and in peribronchial and perivascular inflammatory infiltrates, as previously reported. 29 Airways thus appear as a relevant target for PPAR-c agonists.…”

“…Antibody titers were calculated as the dilution corresponding to twice the mean absorbance value obtained for nonsensitized mouse sera. 29 …”

“…28 We demonstrated that PPARc was expressed by eosinophils and that PPAR-c agonists were able to inhibit eosinophil chemotaxis and antibodydependent cellular cytotoxicity reactions in vitro. 29 Furthermore, in a murine model of asthma, treatment with a PPAR-c agonist also inhibited the development of allergic inflammation, including pulmonary eosinophilia and airway AHR. 29 However, target cells for PPAR-c agonists within the airways and the mechanisms by which they inhibit allergic inflammation are poorly characterized.…”

“…29 Furthermore, in a murine model of asthma, treatment with a PPAR-c agonist also inhibited the development of allergic inflammation, including pulmonary eosinophilia and airway AHR. 29 However, target cells for PPAR-c agonists within the airways and the mechanisms by which they inhibit allergic inflammation are poorly characterized. We reasoned that PPAR-c agonist nebulization might not only affect inflammatory cells, such as eosinophils, mast cells, and T H 2 cells, but also could directly act on airway epithelium and smooth muscle and thus more efficiently contribute to a decreased AHR and remodeling.…”