OBJECTIVE Steroid-resistant airway hyper-responsiveness(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,apreviously 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 viaits anti-oxidative property.METHODS 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.RESULTS 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-γdid not impede nuclear translocation of glucocorticoid receptors but diminishthe protein level of histone deacetylase-2(HDAC2),an essential epigenetic enzymeresponsible for steroid anti-inflammatory action.Andrographolide at low doses(5μmol·L-1 in vitro;1mg·kg-1,ip in vivo)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-2level.CONCLUSION Our data suggest that andrographolide may resensitize steroid action on blocking LPS/IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level. OBJECTIVE Steroid-resistant airway hyper-responsiveness (AHR) has been 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 described 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 viaits anti-oxidative property. METHODS 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 and orographl.mRNA and protein levels of IL-27 in vitro and in vivo were examined, and mouse AHR was assessed. RESULTS 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-in duced IL-27 level in macrophage cell line and primary monocyte / macrophage, mouse bronchoalveolar lavage fluid and lung tissue, and on the incurring AHR. LPS / IFN-γdid not impede nuclear translocation of glucocorticoid receptors but diminish the protein level of histone deacetylase- 2 (HDAC2), an essential epigenetic enzyme responsible for steroid anti-inflammatory action.Andrographolide at low doses (5 μmol·L -1 in vitro; 1 mg · kg -1, ip in vivo) 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-2level. CONCLUSION Our data suggest that andrographolide may resensitize steroid action on blocking LPS / IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level.