title: TNF-α-mediated NF-κB survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells.
abstract: Cisplatin-induced nephrotoxicity is an important limiting factor for cisplatin use. Tumor necrosis factor-α (TNF-α) is known to contribute to cisplatin-induced nephrotoxicity by inducing an inflammatory process aggravating the primary injury, thereby resulting in acute kidney injury (AKI). The present study investigates the pathways synergistically activated by cisplatin and TNF-α responsible for TNF-α-enhanced cisplatin-induced renal cell injury. To do so, immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated with TNF-α and cisplatin. Under these conditions, cisplatin induced dose-dependent apoptosis in IM-PTECs, which was significantly enhanced by TNF-α. Transcriptomic analysis revealed that cisplatin inhibited the typical TNF-α response and cisplatin/TNF-α treatment up-regulated cell death pathways while it down-regulated survival pathways compared to cisplatin alone. In concordance, the gene expression levels of kidney injury markers combined with activation of specific inflammatory mediators were enhanced by cisplatin/TNF-α treatment, resembling the in vivo cisplatin-induced nephrotoxicity response. Furthermore, combined cisplatin/TNF-α treatment inhibited NF-κB nuclear translocation and NF-κB-mediated gene transcription leading to enhanced and prolonged JNK and c-Jun phosphorylation. JNK sustained activation further inhibited NF-κB signaling via a feedback loop mechanism. This led to an alteration in the transcription of the NF-κB-induced anti-apoptotic genes c-IAP2, Bcl-XL, Bruce and Bcl2 and pro-apoptotic genes Bfk and Xaf1 and consequently to sensitization of the IM-PTECs toward cisplatin/TNF-α-induced toxicity. In conclusion, our findings support a model whereby renal cells exposed to both cisplatin and TNF-α switch into a more pro-apoptotic and inflammatory program by altering their NF-κB/JNK/c-Jun balance.
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
authors.forename: Giulia
authors.initials: G
authors.lastname: Benedetti
authors.forename: Lisa
authors.initials: L
authors.lastname: Fredriksson
authors.forename: Bram
authors.initials: B
authors.lastname: Herpers
authors.forename: John
authors.initials: J
authors.lastname: Meerman
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.forename: Marjo
authors.initials: M
authors.lastname: de Graauw
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D004351:Drug Resistance; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin