ABSTRACT
Staphylococcus aureus (S. aureus) infection leads to a severe inflammatory response and causes acute lung injury (ALI), eventually threatening human life. Therefore, it is of importance to find an agent to inhibit inflammation and reduce ALI. Here, we found that costunolide, a sesquiterpene lactone, displays anti-inflammatory effects and ameliorates heat-killed S. aureus (HKSA)-induced pneumonia. Costunolide treatment attenuated HKSA-induced murine ALI in which pulmonary neutrophil infiltration was inhibited, lung edema was decreased, and the production of pro-inflammatory cytokines was significantly reduced. In addition, costunolide dose-dependently inhibited the generation of IL-6, TNF-α, IL-1ß, and keratinocyte-derived cytokine (KC), as well as the expression of iNOS, in HKSA-induced macrophages. Furthermore, costunolide attenuated the phosphorylation of p38 MAPK and cAMP response element-binding protein (CREB). Collectively, our findings suggested that costunolide is a promising agent for alleviating bacterial-induced ALI via the inhibition of the MAPK signaling pathways.
Subject(s)
Acute Lung Injury/drug therapy , Anti-Inflammatory Agents/therapeutic use , Macrophage Activation/drug effects , Sesquiterpenes/therapeutic use , Acute Lung Injury/microbiology , Animals , Cytokines/metabolism , Lung/microbiology , Lung/pathology , MAP Kinase Signaling System/drug effects , Male , Mice, Inbred C57BL , Neutrophil Infiltration/drug effects , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Pneumonia, Staphylococcal/drug therapy , Pneumonia, Staphylococcal/microbiology , Pulmonary Edema/drug therapy , Pulmonary Edema/microbiology , Staphylococcus aureusABSTRACT
BACKGROUND: Linker for activation of T cells (LAT), a transmembrane adaptor protein, plays a role in T cell and mast cell function, while it remains unclear how histone modifications mediate LAT expression in allergic asthma. The present study aimed at understanding alterations of lymphocyte LAT in patients with asthma and potential mechanisms by which histone modulation may be involved in. METHOD: The expression of LAT mRNA was checked by Quantitative real-time PCR and histone hypoacetylation on LAT promoter was detected by Chromatin Immunoprecipitation. RESULTS: Our results demonstrated that the expression of LAT mRNA in peripheral blood T cells from patients with asthma decreased, as compared to healthy controls. Peripheral blood T cells were treated with pCMV-myc-LAT, pCMV-myc or LAT-siRNA plasmid. Over-expression of LAT mRNA and decrease of Th2 cytokine production were noted, which could be prevented by the inhibition of LAT. The further investigation of the role of histone was performed in an asthma model induced by allergen. Histone hypoacetylation on LAT promoter could inhibit LAT expression and enhanced Th2 differentiation, while trichostatin A, a histone deacetylase inhibitor, promoted LAT expression and inhibited Th2 cytokine production. CONCLUSION: Our results indicate that histone hypoacetylation may regulate LAT expression on T cells and modify Th2 polarization in allergic asthma.
