Lipopolysaccharide inhibits TNF-induced apoptosis: Role of nuclear factor-kappa B activation and reactive oxygen intermediates

LPS, a component of the cell wall in Gram-negative bacteria, induces inflam mation and septic shock syndrome by stimulating various inflammatory cytoki nes including TNF. How LPS affects the TNF-mediated cellular responses, how ever, is not understood, In this study, the effect of LPS on TNF-mediated a poptosis in human histiocytic lymphoma U-937 cells was investigated. We fou nd that treatment of cells with LPS completely abolished TNF-mediated cytot oxicity and activation of caspase-3. LPS-chelating antibiotic, polymyxin B, suppressed the antiapoptotic activity, indicating the specificity. of the effect, Within minutes, LPS through CD14 induced the activation of NF-kappa B, degradation of I kappa B alpha (inhibitory subunit of NF-kappa B) and I kappa B beta, and nuclear translocation of p65. An antioxidant, pyrrolidin e dithiocarbamate, which blocked LPS-induced NF-kappa B activation, also ab olished the antiapoptotic effects of LPS at the same time. Besides TNF, the apoptosis induced by taxol and okadaic acid was also sensitive to LPS-indu ced NF-kappa B activation, whereas that induced by H2O2, doxorubicin, dauno mycin, vincristine, and vinblastine was NF-kappa B insensitive. Tumor cells that constitutively expressed NF-kappa B also showed resistance to the apo ptotic effects of TNF, taxol, and okadaic acid, but sensitivity to all othe r agents, indicating the critical role of NF-kappa B in blocking apoptosis induced by certain agents. Overall, these results indicate that LPS induces resistance to the apoptotic effects of TNF and other agents, and that NF-k appa B activation, whether induced or constitutive, inhibits this apoptosis .