Abstract
Steroid-resistant airway hyperresponsiveness (AHR) has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS, IFN-γ and LPS/IFN-γ-stimulated essential mediator IL-27. We investigated whether andrographolide, a previously demonstrated anti-inflammatory bioactive molecule extracted from the plant Andrographis paniculata, could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR via its anti-oxidative property. Mouse macrophage cell line Raw264.7, mouse primary pulmonary monocyte/macrophage, and BALB/c mouse were treated with LPS/IFN-γ, in the presence and absence of increasing doses of dexamethasone and/or andrographolide. mRNA and protein levels of IL-27 in vitro and in vivo were examined, and mouse AHR was assessed. Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 and AHR in mice. Andrographolide significantly facilitated the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 level in macrophage cell line and primary monocyte/macrophage, mouse bronchoalveolar lavage fluid and lung tissue, and furthermore on the incurring AHR. LPS/IFN-γ diminished the protein level of histone deacetylase 2 (HDAC2), an essential epigenetic enzyme responsible for steroid anti-inflammatory action. Andrographolide at low doses restored nuclear HDAC2 protein levels both in cells and in mouse lungs, possibly via suppression of PI3K/Akt signaling pathway and up-regulation of the anti-oxidative transcription factor Nrf-2 level. Our data suggest that andrographolide may resensitize steroid action on blocking LPS/IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level.
- Copyright ©ERS 2015