ACTIVATION AND ATTENUATION OF TRANSCRIPTION FACTOR NF-KB IN MOUSE GLOMERULAR MESANGIAL CELLS IN RESPONSE TO TUMOR-NECROSIS-FACTOR-ALPHA, IMMUNOGLOBULIN-G, AND ADENOSINE 3'/5'-CYCLIC MONOPHOSPHATE - EVIDENCE FOR INVOLVEMENT OF REACTIVE OXYGEN SPECIES
ACTIVATION AND ATTENUATION OF TRANSCRIPTION FACTOR NF-KB IN MOUSE GLOMERULAR MESANGIAL CELLS IN RESPONSE TO TUMOR-NECROSIS-FACTOR-ALPHA, IMMUNOGLOBULIN-G, AND ADENOSINE 3'/5'-CYCLIC MONOPHOSPHATE - EVIDENCE FOR INVOLVEMENT OF REACTIVE OXYGEN SPECIES
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DOI：
10.1172/jci117505
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发表时间：
1994-10-01
影响因子：
15.9
通讯作者：
SCHLONDORFF, D
中科院分区：
文献类型：
--
作者：
SATRIANO, J;SCHLONDORFF, D
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The transcription factor NF-kB may play an important role in the response to tissue injury and activation of cytokines. We therefore examined the regulation of NF-kB in mesangial cells. Treatment of mesangial cells with TNF-alpha increased nuclear proteins that bound to an NF-kB-specific DNA oligonucleotide. IgG aggregates also increased nuclear NF-kB, demonstrating Fc-tau rreceptor-mediated activation of NF-kB. Treatment of a cytosolic preparation with the detergent deoxycholate also activated NF-kB. The binding characteristics were typical for NF-kB transcription factors as determined by competition experiments with NF-kB-binding wild type kB DNA oligonucleotides or mutated oligonucleotides. Furthermore, a monoclonal antibody against the p65 subunit of NF-kB prevented the binding of NF-kB to the kB oligonucleotide. To evaluate the potential role of reactive oxygen intermediates in the activation of NF-kB, we used PDTC as a scavenger and HMAP as an inhibitor of NADPH-dependent oxidase. Both PDTC and HMAP attenuated the increase in nuclear NF-kB in response to either TNF-alpha or IgG complexes. Finally, generation of superoxide anion by xanthine oxidase activated NF-kB, an effect also mitigated by PDTC. In contrast, exogenous H2O2 did not activate NF-kB. Preincubation of cells with 8 br-cAMP, forskolin, or PGE(2) attenuated the increase in nuclear NF-kB in response to TNF-alpha, aggregated IgG, or superoxide anion. Our results provide support for a role of reactive oxygen intermediates as mediators for activation of NF-kB in MC after stimulation with TNP-alpha or IgG aggregates. As an unexpected novel finding we report that cAMP can inhibit activation of NF-kB in MC. These observations may help to explain effects of TNF-alpha, IgG aggregates and cAMP on generation of cytokines by mesangial cells and the resulting glomerular pathophysiology.