THE POTENTIATING EFFECT OF LPS ON TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY INFLUENZA-A VIRUS-INFECTED MACROPHAGES

Infection of murine PU5-1.8 macrophages and human monocytes by influen za A virus was associated with virus replication, release of tumor nec rosis factor-alpha (TNF-alpha) and subsequent cell death. In the prese nce of small and by itself rather inefficient concentrations of lipopo ly-saccharide (LPS) or free lipid A (1 to 10 ng/ml), TNF-alpha product ion of virus-infected macrophages was strongly potentiated. LPS-trigge red and enhanced TNF-alpha release from virus-infected macrophages was neither due to increased cell survival nor altered virus replication, potentiated TNF-alpha gene transcription, release of intracellularly stored TNF-alpha or shifts in the kinetics of TNF-alpha secretion. Inf luenza A virus infection alone induced a massive TNF-alpha mRNA accumu lation which, however, was only weakly translated into bioactive TNF-a lpha protein. When these virus-primed macrophages were exposed to LPS either simultaneously or up to 4h after infection, an efficient and hi gh translation into TNF-alpha protein occurred. Although the LPS-induc ed biochemical pathways leading to an augmented TNF-alpha production b y virus-infected macrophages still remains unsolved, the findings sugg est that the frequently observed serious clinical complications in the course of combined influenza A virus and bacterial infections may be due, at least in part, to an excessive release of cytokines such as TN F-alpha.