In addition, s Mtb induced TNF and IL 6 production was not affected by pretreatment with anti IL 1 Ab. Thus, neither astrocytes nor indirect stimuli such as IL 1 adversely affected the overall findings for primary mixed glial cells. Discussion Given selleck Romidepsin that human microglia are productively infected with Mtb and may be the principal cellular target in the CNS, understanding the molecular mechanisms of microglial activation and the anti microbial response is required to develop targets for therapeutic intervention in CNS TB. Rabbits are an excellent in vivo model for the study of CNS infection and pathogenesis because of their sensitive inflammatory response and their similarity to humans in terms of the clinical and histological symp toms of disease.

Mice are also used to study host immune responses to TB meningitis Inhibitors,Modulators,Libraries because of the advantages in terms of genetic manipulation and the availability of commercial immunological reagents. We demonstrated that murine microglia produces pro inflammatory cytokines in response to s Mtb, and revealed the important roles of MAPK signaling and ROS production in this process. Although ROS signaling con trols a broad range of physiological and pathological processes, including cellular proliferation, inflammation, and apoptosis, our study is the first to Inhibitors,Modulators,Libraries demon strate its role in Inhibitors,Modulators,Libraries microglial activation in response to Mtb. LPS activates both macrophages and microglial cells, which have specific roles in microbial defense within the peripheral and central nervous systems, respectively. Pre viously, Watters et al.

investigated the mechanism of LPS signaling in murine macrophages and microglial cells, and revealed different roles for MAPK signaling in these two cell types. We Inhibitors,Modulators,Libraries also demonstrated that LPS stim ulates the production of TNF , IL 6, and IL 12p40 in murine BV 2 cells and in primary cultures of mixed glial cells, which is consistent with previous studies using pri mary cultures of human, murine, and rat microglial cells. In contrast, very little research has been con ducted regarding the mechanisms of recognition and intracellular signaling that induce the initial immune response to Mtb in microglia. In this study, we prepared non infective Mtb lysates, as described previously by Netea et al. and used them throughout the study. We found that s Mtb strongly activated the inflammatory response and ROS generation in BV 2 microglial cell lines, as in those infected with live Mtb.

In addition, the astrocyte enriched cultures did not play a major role in the s Mtb induced cytokine production and ROS generation by primary mixed glial cells. These find ings are supported by previous findings that the Inhibitors,Modulators,Libraries tubercle bacillus preferentially infects human microglia, rather than astrocytes. The same study also reported that microglial mostly Mtb infection elicited the production of a vari ety of cytokines, including TNF , IL 1 , and IL 6.