NF-KAPPA-B MODULATES LIPOPOLYSACCHARIDE-INDUCED MICROGLIAL NERVE GROWTH-FACTOR EXPRESSION

Microglia/brain macrophages activated in response to injury, infection , or inflammation of the central nervous system (CNS) mediate both neu rotoxic and neurotrophic activities. Although the cytotoxic effects of microglia have been analyzed in detail, little is known about the sig naling pathways involved in microglial neurotrophin expression. Using purified rat microglial cell cultures, the effects of inflammatory age nts such as lipopolysaccharide (LPS) on microglial nerve growth factor (NGF) expression were studied. Application of LPS (0.1-100 ng/ml) ind uced a rapid (2-4 h), dose-dependent increase in NGF mRNA expression f ollowed by enhanced release of NGF protein within 24 h. To determine w hether the transcription factor NF-kappa B, known to be stimulated in activated microglia, is involved in inflammatory mediator-induced NGF expression, we used the NF-kappa B inhibitor pyrrolidine dithiocarbama te (PDTC). Addition of PDTC (100 mu M) to microglia completely abolish ed LPS-induced NGF synthesis, suggesting a key role for NF-kappa B in microglial NGF expression by inflammatory mediators. In conclusion, NF -kappa B-controlled NGF expression by activated microglia appears to c ontribute to the cross-talk between the immune and nervous systems dur ing inflammation in the CNS. (C) 1998 Wiley-Liss, Inc.