Lactate induces tumour necrosis factor‐α, interleukin‐6 and interleukin‐1β release in microglial‐ and astroglial‐enriched primary cultures

Abstract Hyperammonaemia has deleterious effects on the CNS in patients with liver dysfunction. Cellular mechanisms underlying the effects of hyperammonaemia are largely unknown, although astrocytes have been the main target of interest. This study investigated how treatment with NH 4 Cl and lactate, which increase in the brain as a consequence of hyperammonaemia, affects cells in primary rat cultures enriched in either astrocytes or microglia. Morphological changes were studied over time using light microscopy. Release of the proinflammatory cytokines tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6 and IL‐1β was measured using ELISA. NH 4 Cl was found to induce vacuole formation in both culture systems. Lactate treatment altered astrocytic appearance, resulting in increased space between individual cells. Microglia adopted a round morphology with either NH 4 Cl or lactate treatment. Lactate, but not NH 4 Cl, induced release of TNF‐α and IL‐6 in both astroglial‐ and microglial‐enriched cultures, while IL‐1β was released only in microglial cultures. Cytokine release was higher in the microglial‐ than in the astroglial‐enriched cultures. Additionally, the astroglial‐enriched cultures containing approximately 10% microglial cells released more cytokines than cultures containing about 5% microglial cells. Taken together, our data suggest that most TNF‐α, IL‐6 and IL‐1β release comes from microglia. Thus, microglia could play an important role in the pathological process of hyperammonaemia.