Resident brain cells recognize pathogens and can initiate and/or regulate inflammation. Indeed, we have shown that stimulated glial cells rapidly produce inflammatory mediators, followed by the late production of anti-inflammatory cytokines such as IL-10. Here we have investigated the expression and function of other IL-10 family members in resident cells of the CNS, including IL-20 and IL-24. We have demonstrated that murine glial cells express IL-24 in a delayed manner in response to challenge with bacteria or their components. In addition, we have shown that glia constitutively express IL-20/24 receptors, and such expression is elevated in astrocytes following bacterial infection. Importantly, we have demonstrated that IL-24 inhibits the production of inflammatory cytokines by astrocytes and promotes the potentially neuroprotective functions of this cell type. In contrast, glial cells produce IL-20 constitutively and this cytokine acts on astrocytes increasing the expression of canonical inflammatory mediators and priming them for subsequent challenge. Additionally, we have begun to investigate the ability of substance P (SP) to augment the production of cytokines belonging to the IL-10 family. Here we report that non-human primate brain tissue and human glial cells constitutively express the SP receptor. We show that SP can augment the inflammatory and/or neurotoxic responses of human glial cells to disparate and clinically relevant bacterial pathogens. Interestingly, we have also demonstrated that SP can augment the production of the immunosuppressive cytokine, IL-19. Taken together, these data suggest that SP has the potential to affect the initiation and/or resolution of inflammation in human meningitis patients.