The leptomeninges covering the surface of the brain parenchyma play the physical role at the cerebrospinal fluid-blood barrier. We report here that leptomeningeal cells may transduce peripheral proinflammatory signals to the central anti-inflammatory response through the activation of glial cells in the brain parenchyma. After adjuvant injection, both microglia and astrocytes in the cerebral cortex localized in the proximity of the leptomeninges were activated. The protein levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in the cortical extracts were significantly increased at different time after adjuvant injection. The TNF-alpha immunoreactivity was most prominent in the leptomeninges covering astrocytes. On the other hand, the IL-10 immunoreactivity was observed in both activated microglia and astrocytes localized along the leptomeninges. Cultured leptomeningeal cells covering the cerebral cortex released TNF-alpha which was significantly increased by lipopolysaccharide (LPS). Upon stimulation with LPS, cultured leptomeningeal cells also secreted interleukin-1beta and interleukin-6 with differential time-courses. When primary cultured rat astrocytes and microglia were treated with the conditioned medium of LPS-activated cultured leptomeningeal cells, the immunoreactivity of IL-10 was markedly increased. These observations strongly suggest that leptomeningeal cells release pro-inflammatory cytokines to activate both microglia and astrocytes during systemic inflammation. The activated astrocytes and microglia may in turn regulate anti-inflammatory response in the brain by providing IL-10.