Pravastatin attenuates allergic airway inflammation by suppressing antigen sensitisation, interleukin 17 production and antigen presentation in the lung

Abstract

Background: Statins are widely used to treat hyperlipidaemia. Their immunosuppressive effect has recently been confirmed in various immune mediated disease models. However, relatively few studies have been conducted on allergic inflammation, so the precise mechanisms of their actions against allergies have not been fully clarified. On the other hand, the role of interleukin (IL)17 in immune responses has been recently highlighted, but whether statins affect IL17 production has not been well studied. The effect of pravastatin on allergic airway inflammation in a mouse model was examined to elucidate the mechanism of action, focusing on its effect on IL17 production. Methods: BALB/c mice were immunised with ovalbumin (OVA) and then challenged with OVA aerosol. Pravastatin was delivered by intraperitoneal injection during either sensitisation or the challenge. Results: When delivered during systemic sensitisation, pravastatin suppressed OVA induced proliferation and production of Th2 type cytokines such as IL5 in spleen cells ex vivo and in vitro. IL17 production was also suppressed. Furthermore, pavastatin delivered during the inhalation of OVA attenuated eosinophilic airway inflammation, OVA specific IgE production in serum and OVA induced IL17 production in the thoracic lymph node. We also found that pravastatin attenuated the antigen presenting capacity of CD11c + cells obtained from the OVA challenged lung. Conclusion: Pravastatin suppresses the systemic sensitisation to allergen with downregulation of IL17 production. It also suppresses an ongoing immune response in the airway partly by suppressing antigen presentation in the lung. Therefore, statins could be a novel therapeutic option for treatment of asthma.Statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and have been widely prescribed to treat hyperlipidaemia. Large clinical trials have demonstrated that statins can be used for primary and secondary prevention of cardiovascular diseases.

Alendronate Attenuates Eosinophilic Airway Inflammation Associated with Suppression of Th2 Cytokines, Th17 Cytokines, and Eotaxin-2

“…Both of them are inhibitors of the mevalonate pathway. We previously reported that pravastatin suppressed eosinophilic airway inflammation by attenuating the function of CD11c + APCs (mainly dendritic cells and partly macrophages) in the lung (10). There are also in vitro reports showing that zoledronic acid, another N-BP, inhibited the function of dendritic cells by altering their differentiation and maturation (52,53).…”

“…Mouse IL-17 was measured by ELISA using a purified rat anti-mouse IL-17 mAb for capture and biotinylated rat anti-mouse IL-17 mAb for detection (BD Pharmingen) (10). The titers of samples for IL-17 were calculated by comparisons with internal standards.…”

“…For example, several studies have been conducted using simvastatin (7,8) or pravastatin (9) in models of allergic airway inflammation. We also showed that pravastatin suppressed allergic airway inflammation partly by suppressing the Ag-presenting capacity of dendritic cells (10). Based on their similar mechanism of action to statins, N-BPs may affect allergic airway inflammation; however, this possibility has not yet been examined.…”

Upregulation of geranylgeranyltransferase I in bronchial smooth muscle of mouse experimental asthma: its inhibition by lovastatin

“…Preparation of a murine model of allergic bronchial asthma was performed as described previously (Chiba et al, 2005;2009). In brief, mice (8 weeks of age) were actively sensitized by intraperitoneal injections of 8 µg ovalbumin (OA; Seikagaku Co., Tokyo, Japan) with 2 mg Imject Alum (Pierce Biotechnology, Inc., Rockfold, IL, USA) on days 0 and 5.…”

“…Twenty-four hour after the last OA challenge, mice were sacrificed by exsanguination from abdominal aorta under urethane (1.6 g/kg, i.p. ; Sigma-Aldrich, St. Louis, MO, USA) anesthesia, and protein samples of BSM tissues were prepared as previously described (Chiba et al, 2005;2009).…”