Molecular Mechanisms for Lipopolysaccharide-induced Biphasic Activation of Nuclear Factor-κB (NF-κB)*

The nuclear factor-κB (NF-κB) is an important transcription factor necessary for initiating and sustaining inflammatory and immune reactions. The inducers of NF-κB are well characterized, but the molecular mechanisms underlying multiplein vivo NF-κB activation processes are poorly understood. The injection of lipopolysaccharide resulted in a biphasic activation of NF-κB during the 18-h observation period in various organs of mice. The early and late phases of NF-κB activation occurred at 0.5–2 h and 8–12 h, respectively. Platelet-activating factor, which is released in response to lipopolysaccharide injection, was responsible for the activation of the early phase of NF-κB. The early NF-κB activity led to the induction of proinflammatory cytokines, tumor necrosis factor (TNF), and interleukin (IL)-1β, which are known to be efficient inducers of NF-κB. Using the TNF knockout and IL-1 receptor knockout mice, we found that TNF and IL-1β had a role in the second phase activation of NF-κB. These cytokines did promote the synthesis of platelet-activating factor, which in turn induced the secondary activation of NF-κB. These observations describe a novel autoregulatory molecular mechanism for the biphasic activation of NF-κB.