Pro-caspase-3 protects cells from polymyxin B-induced cytotoxicity by preventing ROS accumulation

Yokosawa, Takumi; Yamada, Mihoko; Noguchi, Takuya; Suzuki, Saki; Hirata, Yusuke; Matsuzawa, Atsushi

doi:10.1038/s41429-019-0216-6

Cited by 18 publications

(13 citation statements)

References 18 publications

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“…NLRP3, ASC, caspase-1, and caspase-3 knockout cells were generated using the CRISPR/Cas9 system as previously described 66,67 . Guide RNAs (gRNAs) were designed to target a region in the exon 1 of NLRP3 gene (5ʹ-CTGCAAGCTGGCCAGGTACC-3ʹ), the exon 1 of ASC gene (5ʹ-CAGCACGTTAGCGGTGAGCT-3ʹ), the exon 2 of caspase-1 gene (5ʹ-AAGCTGTTTATCCGTTC CAT-3ʹ), and the exon 5 of caspase-3 gene (5ʹ-CATAC ATGGAAGCGAATCAATGG-3ʹ) using CRISPRdirect.…”

Section: Generation Of Ko Cellsmentioning

confidence: 99%

“…Guide RNAs (gRNAs) were designed to target a region in the exon 1 of NLRP3 gene (5ʹ-CTGCAAGCTGGCCAGGTACC-3ʹ), the exon 1 of ASC gene (5ʹ-CAGCACGTTAGCGGTGAGCT-3ʹ), the exon 2 of caspase-1 gene (5ʹ-AAGCTGTTTATCCGTTC CAT-3ʹ), and the exon 5 of caspase-3 gene (5ʹ-CATAC ATGGAAGCGAATCAATGG-3ʹ) using CRISPRdirect. gRNA-encoding oligonucleotide was cloned into lenti-CRISPRv2 plasmid (addgene), and knockout cells were established as previously described 66,67 . To determine the mutations of each gene in cloned cells, genomic sequence around the target region was analyzed by PCR-direct sequencing using extracted DNA from each clone as a template and the following primers: 5ʹ-AGTGTGGACC-GAAGCCTAAG-3ʹ and 5ʹ-TTCTCCTCCCCATTGAAG TC-3ʹ for NLRP3; 5ʹ-TTGGACCTCACCGACAAG-3ʹ and 5ʹ-GCAGCTTTGTTTAGGGGTAGG-3ʹ for ASC; 5ʹ-TA CCCAACTGTGAGGAGGGG-3ʹ and 5ʹ-TGGCCCTGA AGCCAGAAATAA-3ʹ for caspase-1, 5ʹ-GCAGCTTTG TTTAGGGGTAGG-3ʹ for ASC; 5ʹ-ACAGAAGGCGTG GTCATTTC-3ʹ and 5ʹ-TGTAGGTCCTGCCCAATCT C-3ʹ for caspase-3.…”

Section: Generation Of Ko Cellsmentioning

confidence: 99%

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Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms

et al. 2021

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Anticancer drug gefitinib causes inflammation-based side effects, such as interstitial pneumonitis. However, its mechanisms remain unknown. Here, we provide evidence that gefitinib elicits pro-inflammatory responses by promoting mature-interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release. Mitochondrial reactive oxygen species (mtROS) driven by gefitinib stimulated the formation of the NLRP3 (NACHT, LRR and PYD-containing protein 3) inflammasome, leading to mature-IL-1β release. Notably, gefitinib also stimulated HMGB1 release, which is, however, not mediated by the NLRP3 inflammasome. On the other hand, gefitinib-driven mtROS promoted the accumulation of γH2AX, a hallmark of DNA damage, leading to the activation of poly (ADP-ribose) polymerase-1 (PARP-1) and subsequent active release of HMGB1. Together our results reveal the potential ability of gefitinib to initiate sterile inflammation via two distinct mechanisms, and identified IL-1β and HMGB1 as key determinants of gefitinib-induced inflammation that may provide insights into gefitinib-induced interstitial pneumonitis.

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Section: Generation Of Ko Cellsmentioning

confidence: 99%

Section: Generation Of Ko Cellsmentioning

confidence: 99%

Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms

et al. 2021

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“…4) Indeed, in HT1080 cells, our recent study has demonstrated that the pharmacological inhibition of Nrf2 exacerbates the cytotoxicity induced by polymyxin B, a polypeptide antibiotic that causes undesirable cytotoxic side effects. 17) In a manner similar to ROS generation, we observed that CTX promotes nuclear translocation of Nrf2, a hallmark of its activation, even if the nontoxic concentrations of CTX (200 or 400 μg/mL) are treated ( Fig. 2A).…”

Section: Nontoxic Concentration Of Ctx Activates the Nrf2 Signaling Pmentioning

confidence: 66%

The Antibiotic Cefotaxime Works as Both an Activator of Nrf2 and an Inducer of HSP70 in Mammalian Cells

et al. 2020

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Both NF-E2-related factor 2 (Nrf2) and heat shock protein 70 (HSP70) contribute to cellular defense to various stresses, and have emerged as candidates of therapeutic targets to improve or prevent tissue damage. Cefotaxime (CTX), a third-generation cephalosporin antibiotic, is conceived as a safe drug largely free from side effects. CTX exhibits broad-spectrum antimicrobial activity, and thereby, is most commonly prescribed for the treatment of infectious diseases induced by Gram-positive or Gram-negative bacteria. In this study, we unexpectedly found the beneficial properties of CTX that upregulate both Nrf2 and HSP70 to the extent that stressinduced damage is ameliorated. Non-toxic levels of reactive oxygen species (ROS) induced by CTX activated the Nrf2 pathway without cytotoxicity, which in turn upregulated HSP70. Interestingly, the cytotoxicity of Fas/ CD95 ligand (FasL), a cytotoxic cytokine that strongly induces apoptosis, was significantly ameliorated by pretreatment with CTX, most likely because of the upregulation of Nrf2 and HSP70. Our results therefore show novel properties of CTX, which raise the possibility that CTX works as a non-toxic therapeutic agent for preventing and repairing tissue damage.

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“…ROS detection assay was performed as described previously [ 40 ]. RAW264.7 cells or BMDMs were seeded on glass plates.…”

Section: Methodsmentioning

confidence: 99%

TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms

Suzuki

Asai

Kagi

et al. 2020

IJMS

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It is known that a wide variety of antibacterial agents stimulate generation of reactive oxygen species (ROS) in mammalian cells. However, its mechanisms are largely unknown. In this study, we unexpectedly found that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is involved in the generation of mitochondrial ROS (mtROS) initiated by cefotaxime (CTX), one of specific antibacterial cephalosporins that can trigger oxidative stress-induced cell death. TAK1-deficient macrophages were found to be sensitive to oxidative stress-induced cell death stimulated by H2O2. Curiously, however, TAK1-deficient macrophages exhibited strong resistance to oxidative stress-induced cell death stimulated by CTX. Microscopic analysis revealed that CTX-induced ROS generation was overridden by knockout or inhibition of TAK1, suggesting that the kinase activity of TAK1 is required for CTX-induced ROS generation. Interestingly, pharmacological blockade of the TAK1 downstream pathways, such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, did not affect the CTX-induced ROS generation. In addition, we observed that CTX promotes translocation of TAK1 to mitochondria. Together, these observations suggest that mitochondrial TAK1 mediates the CTX-induced mtROS generation through noncanonical mechanisms. Thus, our data demonstrate a novel and atypical function of TAK1 that mediates mtROS generation triggered by the specific cephalosporins.

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Pro-caspase-3 protects cells from polymyxin B-induced cytotoxicity by preventing ROS accumulation

Cited by 18 publications

References 18 publications

Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms

Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms

The Antibiotic Cefotaxime Works as Both an Activator of Nrf2 and an Inducer of HSP70 in Mammalian Cells

TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms

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