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Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis.
Hepatology. 2011 Jun; 53(6):2027-41.Hep

Abstract

Drug-induced liver injury (DILI) is an important clinical problem. It involves crosstalk between drug toxicity and the immune system, but the exact mechanism at the cellular hepatocyte level is not well understood. Here we studied the mechanism of crosstalk in hepatocyte apoptosis caused by diclofenac and the proinflammatory cytokine tumor necrosis factor α (TNF-α). HepG2 cells were treated with diclofenac followed by TNF-α challenge and subsequent evaluation of necrosis and apoptosis. Diclofenac caused a mild apoptosis of HepG2 cells, which was strongly potentiated by TNF-α. A focused apoptosis machinery short interference RNA (siRNA) library screen identified that this TNF-α-mediated enhancement involved activation of caspase-3 through a caspase-8/Bid/APAF1 pathway. Diclofenac itself induced sustained activation of c-Jun N-terminal kinase (JNK) and inhibition of JNK decreased both diclofenac and diclofenac/TNF-α-induced apoptosis. Live cell imaging of GFPp65/RelA showed that diclofenac dampened the TNF-α-mediated nuclear factor kappaB (NF-κB) translocation oscillation in association with reduced NF-κB transcriptional activity. This was associated with inhibition by diclofenac of the TNF-α-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα). Finally, inhibition of IκB kinase β (IKKβ) with BMS-345541 as well as stable lentiviral short hairpin RNA (shRNA)-based knockdown of p65/RelA sensitized hepatocytes towards diclofenac/TNF-α-induced cytotoxicity.

CONCLUSION

Together, our data suggest a model whereby diclofenac-mediated stress signaling suppresses TNF-α-induced survival signaling routes and sensitizes cells to apoptosis.

Authors+Show Affiliations

Division of Toxicology, Leiden/Amsterdam Centre for Drug Research, Leiden University, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21433042

Citation

Fredriksson, Lisa, et al. "Diclofenac Inhibits Tumor Necrosis Factor-α-induced Nuclear factor-κB Activation Causing Synergistic Hepatocyte Apoptosis." Hepatology (Baltimore, Md.), vol. 53, no. 6, 2011, pp. 2027-41.
Fredriksson L, Herpers B, Benedetti G, et al. Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis. Hepatology. 2011;53(6):2027-41.
Fredriksson, L., Herpers, B., Benedetti, G., Matadin, Q., Puigvert, J. C., de Bont, H., Dragovic, S., Vermeulen, N. P., Commandeur, J. N., Danen, E., de Graauw, M., & van de Water, B. (2011). Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis. Hepatology (Baltimore, Md.), 53(6), 2027-41. https://doi.org/10.1002/hep.24314
Fredriksson L, et al. Diclofenac Inhibits Tumor Necrosis Factor-α-induced Nuclear factor-κB Activation Causing Synergistic Hepatocyte Apoptosis. Hepatology. 2011;53(6):2027-41. PubMed PMID: 21433042.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis. AU - Fredriksson,Lisa, AU - Herpers,Bram, AU - Benedetti,Giulia, AU - Matadin,Quraisha, AU - Puigvert,Jordi C, AU - de Bont,Hans, AU - Dragovic,Sanja, AU - Vermeulen,Nico P E, AU - Commandeur,Jan N M, AU - Danen,Erik, AU - de Graauw,Marjo, AU - van de Water,Bob, PY - 2011/3/25/entrez PY - 2011/3/25/pubmed PY - 2011/8/30/medline SP - 2027 EP - 41 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 53 IS - 6 N2 - UNLABELLED: Drug-induced liver injury (DILI) is an important clinical problem. It involves crosstalk between drug toxicity and the immune system, but the exact mechanism at the cellular hepatocyte level is not well understood. Here we studied the mechanism of crosstalk in hepatocyte apoptosis caused by diclofenac and the proinflammatory cytokine tumor necrosis factor α (TNF-α). HepG2 cells were treated with diclofenac followed by TNF-α challenge and subsequent evaluation of necrosis and apoptosis. Diclofenac caused a mild apoptosis of HepG2 cells, which was strongly potentiated by TNF-α. A focused apoptosis machinery short interference RNA (siRNA) library screen identified that this TNF-α-mediated enhancement involved activation of caspase-3 through a caspase-8/Bid/APAF1 pathway. Diclofenac itself induced sustained activation of c-Jun N-terminal kinase (JNK) and inhibition of JNK decreased both diclofenac and diclofenac/TNF-α-induced apoptosis. Live cell imaging of GFPp65/RelA showed that diclofenac dampened the TNF-α-mediated nuclear factor kappaB (NF-κB) translocation oscillation in association with reduced NF-κB transcriptional activity. This was associated with inhibition by diclofenac of the TNF-α-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα). Finally, inhibition of IκB kinase β (IKKβ) with BMS-345541 as well as stable lentiviral short hairpin RNA (shRNA)-based knockdown of p65/RelA sensitized hepatocytes towards diclofenac/TNF-α-induced cytotoxicity. CONCLUSION: Together, our data suggest a model whereby diclofenac-mediated stress signaling suppresses TNF-α-induced survival signaling routes and sensitizes cells to apoptosis. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/21433042/Diclofenac_inhibits_tumor_necrosis_factor_α_induced_nuclear_factor_κB_activation_causing_synergistic_hepatocyte_apoptosis_ L2 - https://doi.org/10.1002/hep.24314 DB - PRIME DP - Unbound Medicine ER -