Microglia/brain macrophages activated in response to injury, infection, or inflammation of the central nervous system (CNS) mediate both neurotoxic and neurotrophic activities. Although the cytotoxic effects of microglia have been analyzed in detail, little is known about the signaling pathways involved in microglial neurotrophin expression. Using purified rat microglial cell cultures, the effects of inflammatory agents such as lipopolysaccharide (LPS) on microglial nerve growth factor (NGF) expression were studied. Application of LPS (0.1-100 ng/ml) induced a rapid (2-4 h), dose-dependent increase in NGF mRNA expression followed by enhanced release of NGF protein within 24 h. To determine whether the transcription factor NF-kappaB, known to be stimulated in activated microglia, is involved in inflammatory mediator-induced NGF expression, we used the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC). Addition of PDTC (100 microM) to microglia completely abolished LPS-induced NGF synthesis, suggesting a key role for NF-kappaB in microglial NGF expression by inflammatory mediators. In conclusion, NF-kappaB-controlled NGF expression by activated microglia appears to contribute to the cross-talk between the immune and nervous systems during inflammation in the CNS.