Involvement of nuclear factor‐xB in platelet‐activating factor‐mediated tumor necrosis factor‐α expression

摘要

AbstractTumor necrosis factor (TNF)‐α and platelet‐activating factor (PAF) are important mediators of inflammatory reactions, and their release is controlled by a positive feedback network. However, the regulatory mechanisms underlying the interaction of these two molecules are unknown. Within 10 min of the injection of lipopolysaccharide (LPS) into C57BL/6 mice, effects inducible by PAF such as anaphylactic shock‐like symptoms, disseminated intravascular coagulation, and hemorrhage in renal medullae were observed, and all these pathological changes were prevented by the PAF antagonist, BN 50739. The plasma level of PAF after LPS injection reached a peak at 5 min. TNF‐α gene expression was evident 20 min after LPS injection and was maximal at 40 min, and the level of serum TNF‐α reached a peak at 1 h. Pretreatment with BN 50739 inhibited LPS‐induced TNF‐α gene expression and protein synthesis in a dose‐dependent manner. Injection of PAF or treatment of the macrophage cell line, J774A.1, with PAF activated the transcription factor, nuclear factor (NF)‐xB, which is essential for inducible TNF‐α transcription. The activation of NF‐xB by PAF preceded the LPS‐mediated TNF‐α gene expression. Pretreatment with BN 50739 inhibited LPS‐induced mobilization of NF‐xB in a dose‐dependent mannerin vivoas well asin vitro. These data suggest that PAF, which is released immediately or shortly after LPS injection, induces the expression of