Molecular immunology
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Molecular immunology · Jul 2009
Specificity of the zebrafish host transcriptome response to acute and chronic mycobacterial infection and the role of innate and adaptive immune components.
Pathogenic mycobacteria have the ability to survive within macrophages and persist inside granulomas. The complex host-pathogen interactions that determine the outcome of a mycobacterial infection process result in marked alterations of the host gene expression profile. Here we used the zebrafish model to investigate the specificity of the host response to infections with two mycobacterium strains that give distinct disease outcomes: an acute disease with early lethality or a chronic disease with granuloma formation, caused by Mycobacterium marinum strains Mma20 and E11, respectively. ⋯ We also found that nearly 1000 mycobacterium-responsive genes overlapped between the expression signatures of infected zebrafish adults and embryos at different stages of granuloma formation. Since adult zebrafish possess an adaptive immune system similar to mammals and zebrafish embryos rely solely on innate immunity, this overlap indicates a major contribution of the innate component of the immune system in the response to mycobacterial infection. Taken together, our comparison of the transcriptome responses involved in acute versus chronic infections and in the embryonic versus adult situation provides important new leads for investigating the mechanism of mycobacterial pathogenesis.
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Molecular immunology · Jul 2009
Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-alpha expression in macrophages by reducing IL-10 expression.
Bacterial lipopolysaccharide (LPS) induces monocytes/macrophages to express proinflammatory cytokines and tissue factor (TF), the primary activator of the coagulation cascade. Anti-inflammatory signaling pathways including the phosphatidylinositol-3-kinase (PI3K)-Akt pathway inhibit proinflammatory and TF gene expression in macrophages. We determined the role of Akt, the mammalian target of rapamycin (mTOR) and interleukin-10 in the inhibition of LPS-induced proinflammatory cytokine and TF gene expression in peritoneal macrophages (PMs). ⋯ However, the neutralizing IL-10 antibody did not completely prevent inhibition of LPS-induced TNFalpha and TF expression in PTEN(-/-) PMs. The results indicate that mTOR dependent IL-10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokine TNFalpha in WT macrophages. In contrast, the decrease in LPS-induced TNFalpha and TF expression in PTEN(-/-) PMs also requires an IL-10-independent pathway.