The canonical mechanistic pathway from IPA was used to identify plausible regulatory factors that are co Wortmannin mTOR regulated by STAT1 to elicit Inhibitors,Modulators,Libraries the observed changes in the level of expression of target genes. As shown in Figure 4A, STAT1 interacts with 17 regulators, of which only 3 were differentially expressed Inhibitors,Modulators,Libraries in both HN878 and CDC1551 infected rabbit lungs. STAT1, IRF1 and NFKB1A were expressed at 14. 2, 5. 4, and 1. 9 fold higher levels in HN878 infected lungs, relative to uninfected rabbit lungs. In contrast, expres sion of JUN was upregulated 3. 6 fold in the CDC1551 infected lungs, compared to uninfected rabbit lungs. Next, we interrogated the SDEG to identify the target genes of the STAT1 mechanistic network.
Among the 261 SDEG involved in the STAT1 mechanistic net work, the expression of 194 and 157 genes were upregulated in HN878 and CDC1551 infected rabbit lungs, respectively. To decipher the activation status of the Inhibitors,Modulators,Libraries STAT1 network, we analyzed the direction of ex pression of STAT1 interaction network genes. These genes are a subset of the 261 SDEG present in the mechanistic network. Interestingly, 41 out of 42 genes in this network were upregulated during HN878 infec tion, compared to only 22 in CDC1551 infected lungs. Importantly, the direction of expres sion of these genes showed an early and robust activation of the STAT1 network in only the HN878 and not in the CDC1551 infected rabbit lungs at 3 hours. The ex pression pattern of all target genes of the STAT1 interaction network in the HN878 infected rabbit lungs is consistent with the IPA predicted activation of the STAT1 network, based on experimentally ob served causal effect between the regulators and target genes.
Gene expression in selected networks affected by Mtb infection of rabbit lungs To better understand the causal link Inhibitors,Modulators,Libraries underlying the dif ferential induction of the inflammatory response and STAT1 regulon networks, we studied gene networks involved in macrophage activation, fMLP stimulation and recruitment and activation of PMN in infected rabbit lungs. The macrophage activation network con tains a subset of 33 SDEG that encode cytokines and chemokines, cell surface re ceptors, enzymes and transcriptional regulators. At 3 hours post infection, most of the macrophage activation network genes were upregulated in HN878 infected Inhibitors,Modulators,Libraries lungs, relative to those infected with CDC1551.
In con trast, a higher number of SDEG were downregulated selleck bio in rabbit lungs following CDC1551 infection. Among the 14 upregulated genes in the CDC1551 infected animals relative to uninfected lungs, 9 genes were expressed at much higher levels than those observed in the lungs of HN878 infected rab bits. fMLP is a chemoattractant peptide, produced by acti vated cells of the immune system, which stimulates recruited immune cells to produce proinflammatory molecules.
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