ENHANCEMENT OF LIPOPOLYSACCHARIDE-INDUCED NEUTROPHIL OXYGEN RADICAL PRODUCTION BY TUMOR-NECROSIS-FACTOR-ALPHA

Although tissues become exposed to both exogenous and endogenous cell- activating mediators during infection, there is little appreciation of the effects of subjecting cells to multiple mediators. We examined th e hypothesis that the response of neutrophils to bacterial lipopolysac charide (LPS) is significantly altered in the presence of the endogeno us mediator tumor necrosis factor alpha (TNF). The data showed that hu man neutrophils pretreated with TNF for 10 to 30 min, displayed signif icantly enhanced superoxide production in response to LPS (from either Escherichia coli K-235 or E. coli O127:B8), measured as lucigenin-dep endent chemiluminescence (CL), seen as an increase in the initial peak rate as well as the total CL accumulated over the incubation period. TNF amplified the response to LPS at 1 to 100 U of TNF/10(6) neutrophi ls and was able to enhance the response to a aide range of concentrati ons of LPS (0.01 to 1,000 ng/ml). The TNF-induced increase in the LPS response was paralleled by an increase in LPS binding to the neutrophi ls, which could be abrogated by an anti-CD14 monoclonal antibody, The results demonstrate that TNF significantly increases the LPS-induced r elease of oxygen radicals in neutrophils through the upregulation of c ell surface CD14.