Pre treatment with anti IL 1 Ab did Brefeldin A not affect the s Mtb induced ROS generation or cytokine production, suggest ing that the results for primary mixed glial cultures were specific to s Mtb. The mechanisms resulting in tissue destruction in TB meningitis are currently unclear. However, growing evi dence suggests that inflammatory responses in the brain lead to tissue destruction in the distinct immunological setting of the CNS. Roles for Mtb induced proinflam matory cytokines and chemokines in CNS TB have been suggested because dexamethasone treatment suppresses the production of pro inflammatory cytokines and Inhibitors,Modulators,Libraries chem okines in Mtb infected human microglia. It may explain the beneficial effects of this adjunctive therapy with steroids on the outcome of TB meningitis. Fur thermore, recent studies by Harris et al.
showed that treating human astrocytes with conditioned Inhibitors,Modulators,Libraries medium from Mtb infected monocytes significantly up regulated matrix metalloproteinase 9, which suggests that Mtb may increase the activity of tissue destructive matrix metallo proteinases. Therefore, pro inflammatory mediators Inhibitors,Modulators,Libraries or tissue destructive enzymes could contribute to the neuro logical damage observed in CNS TB. Our data clearly demonstrate that the activation of p47phox and MAPK is mutually dependent on inflamma tory signaling in s Mtb stimulated microglia. The results indicate that ROS formation occurs immediately after s Mtb stimulation and that ROS act as signaling molecules in MAPK activation and subsequent processes.
Possible redox dependent signaling leading to MAPK activation includes the H2O2 mediated inactivation of phosphatase and the deletion of the tensin homologue on chromosome 10. In addition, ROS Inhibitors,Modulators,Libraries mediate calcium release, as all three MAPKs are downstream of calcium dependent processes. These studies and our data suggest that the NADPH oxidase derived ROS operate upstream of MAPKs. In addi tion, the data demonstrate that MAPK activation is required for the phosphorylation of p47phox and ROS production in microglial cells. The phosphorylation of p47phox at sev eral serine residues within the polybasic region of the pro tein is an essential step in the activation of the NADPH oxidase complex. Previous studies have shown that p47phox is a good in vitro substrate for ERK2 and p38 MAPK, and that the phosphorylation Inhibitors,Modulators,Libraries our site of p47phox on Ser345 is directly related to GM CSF and TNF induced priming of ROS production. Taken together, the crosstalk between p47phox and MAPK activation may play a pivotal role in the induction of ROS dependent inflammatory responses by microglial cells. Although they play different roles, both IL 12 and TNF are critical factors in the defense against mycobacteria. IL 12 is crucial for the differentiation of IFN producing Th1 cells.
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