Manna S K, Aggarwal B B
Cytokine Research Laboratory, Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
J Immunol. 1999 Feb 1;162(3):1510-8.
LPS, a component of the cell wall in Gram-negative bacteria, induces inflammation and septic shock syndrome by stimulating various inflammatory cytokines including TNF. How LPS affects the TNF-mediated cellular responses, however, is not understood. In this study, the effect of LPS on TNF-mediated apoptosis in human histiocytic lymphoma U-937 cells was investigated. We found that treatment of cells with LPS completely abolished TNF-mediated cytotoxicity 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-kappaB, degradation of IkappaBalpha (inhibitory subunit of NF-kappaB) and IkappaBbeta, and nuclear translocation of p65. An antioxidant, pyrrolidine dithiocarbamate, which blocked LPS-induced NF-kappaB activation, also abolished the antiapoptotic effects of LPS at the same time. Besides TNF, the apoptosis induced by taxol and okadaic acid was also sensitive to LPS-induced NF-kappaB activation, whereas that induced by H2O2, doxorubicin, daunomycin, vincristine, and vinblastine was NF-kappaB insensitive. Tumor cells that constitutively expressed NF-kappaB also showed resistance to the apoptotic effects of TNF, taxol, and okadaic acid, but sensitivity to all other agents, indicating the critical role of NF-kappaB 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-kappaB activation, whether induced or constitutive, inhibits this apoptosis.
脂多糖（LPS）是革兰氏阴性菌细胞壁的一种成分，通过刺激包括肿瘤坏死因子（TNF）在内的多种炎性细胞因子，引发炎症反应和脓毒性休克综合征。然而，LPS如何影响TNF介导的细胞反应尚不清楚。在本研究中，我们调查了LPS对人组织细胞淋巴瘤U - 937细胞中TNF介导的细胞凋亡的影响。我们发现，用LPS处理细胞完全消除了TNF介导的细胞毒性和半胱天冬酶 - 3的激活。LPS螯合抗生素多粘菌素B抑制了这种抗凋亡活性，表明了该效应的特异性。在几分钟内，LPS通过CD14诱导核因子κB（NF - κB）的激活、IκBα（NF - κB的抑制亚基）和IκBβ的降解以及p65的核转位。一种抗氧化剂吡咯烷二硫代氨基甲酸盐可阻断LPS诱导的NF - κB激活，同时也消除了LPS的抗凋亡作用。除了TNF外，紫杉醇和冈田酸诱导的细胞凋亡也对LPS诱导的NF - κB激活敏感，而过氧化氢、阿霉素、柔红霉素、长春新碱和长春花碱诱导的细胞凋亡对NF - κB不敏感。组成性表达NF - κB的肿瘤细胞对TNF、紫杉醇和冈田酸的凋亡作用也表现出抗性，但对所有其他药物敏感，表明NF - κB在阻断某些药物诱导的细胞凋亡中起关键作用。总体而言，这些结果表明，LPS诱导对TNF和其他药物凋亡作用的抗性，并且NF - κB激活，无论是诱导性的还是组成性的，都抑制这种细胞凋亡。
