lipoteichoic-acid and Chemical-and-Drug-Induced-Liver-Injury

Lipoteichoic acid (LTA)-induced acute lung injury (ALI) is an experimental model for mimicking Gram-positive bacteria-induced pneumonia that is a refractory disease with lack of effective medicines. Here, we reported that costunolide, a sesquiterpene lactone, ameliorated LTA-induced ALI. Costunolide treatment reduced LTA-induced neutrophil lung infiltration, cytokine and chemokine production (TNF-α, IL-6 and KC), and pulmonary edema. In response to LTA challenge, treatment with costunolide resulted less iNOS expression and produced less inflammatory cytokines in bone marrow derived macrophages (BMDMs). Pretreatment with costunolide also attenuated the LTA-induced the phosphorylation of p38 MAPK and ERK in BMDMs. Furthermore, costunolide treatment reduced the phosphorylation of TAK1 and inhibited the interaction of TAK1 with Tab1. In conclusion, we have demonstrated that costunolide protects against LTA-induced ALI via inhibiting TAK1-mediated MAPK signaling pathway, and our studies suggest that costunolide is a promising agent for treatment of Gram-positive bacteria-mediated pneumonia.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytokines; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Gram-Positive Bacteria; Humans; Inflammation Mediators; Lipopolysaccharides; Lung; Macrophages; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Pneumonia, Bacterial; Pulmonary Edema; Sesquiterpenes; Signal Transduction; Teichoic Acids

Lipopolysaccharide (LPS) tolerance is a state of refractoriness towards a second stimulation by LPS after a preceding stimulation. LPS is recognized by Toll-like receptor-4 (TLR-4), which belongs to a group of pattern recognition receptors mediating activation of innate immunity by microbial components. To date, it is not known in detail to what extent other TLR-dependent stimuli also induce tolerance and whether preceding and challenging stimuli are interchangeable. We have examined tolerance induction in detail for lipoteichoic acid (LTA), LPS and CpG-DNA, which are recognized by TLR-2, -4 and -9, respectively. In RAW264.7 macrophages, all three stimuli induced tolerance towards a subsequent challenge with the same stimulus used for priming, as well as cross-tolerance towards subsequent challenge with other stimuli signalling via different TLRs. However, whereas LPS/LTA cross-tolerance was also functional in an in vivo model of galactosamine (GalN)-primed liver damage, pretreatment with CpG only protected against GalN/CpG challenge and failed to induce cross-tolerance for LPS and LTA. CpG-DNA pretreatment even enhanced tumour necrosis factor (TNF)-alpha production and liver damage upon subsequent challenge with LPS or LTA. Stimulation with CpG-DNA resulted in a peculiar sensitization for interferon (IFN)-gamma secretion. The data indicate that, in contrast to in vitro macrophage desensitization, the in vivo consequences of repeated TLR stimulation greatly differ amongst different TLR ligands.

Topics: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; CpG Islands; DNA-Binding Proteins; Immune Tolerance; Interferon-gamma; Interleukin-18; Ligands; Lipopolysaccharides; Macrophages, Peritoneal; Membrane Glycoproteins; Mice; Mice, Inbred Strains; Oligodeoxyribonucleotides; Receptors, Cell Surface; Receptors, Immunologic; Teichoic Acids; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9; Toll-Like Receptors