Interleukin-6 sensitizes TNF-α and TRAIL/Apo2L dependent cell death through upregulation of death receptors in human cancer cells

Emiko Sano, Akira Kazaana, Hisashi Tadakuma, Toshiaki Takei, Sodai Yoshimura, Yuya Hanashima, Yoshinari Ozawa, Atsuo Yoshino, Yutaka Suzuki, Takuya Ueda

Research output: Contribution to journalArticlepeer-review


Interleukin-6 (IL-6) enhanced TNF-α and TRAIL/Apo2L induced cell death in various human cancer cells derived from malignant glioma, melanoma, breast cancer and leukemia, although the effect was not detected with IL-6 alone. The effects of IL-6 using SKBR3 cells were associated with the generation of apoptotic cells as analyzed by fluorescence microscopy and flow cytometry. IL-6 activated p53 and upregulated TRAIL death receptors (DR-4 and DR-5) and stimulated the TNF-α and TRAIL dependent extrinsic apoptotic pathway without activation of the p53 mediated intrinsic apoptotic pathway. TNF-α and TRAIL induced cleavage of caspase-8 and caspase-3 was more enhanced by IL-6, although these caspases were not cleaved by IL-6 alone. The dead cell generation elicited by the combination with IL-6 was blocked by anti-human TRAIL R2/TNFRSF10B Fc chimera antibody which can neutralize the DR-5 mediated death signal. These findings indicate that IL-6 could contribute to the enhancement of TNF-α or TRAIL induced apoptosis through p53 dependent upregulation of DR-4 and DR-5. The data suggest that a favorable therapeutic interaction could occur between TNF-α or TRAIL and IL-6, and provide an experimental basis for rational clinical treatments in various cancers.

Original languageEnglish
Article number119037
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number7
Publication statusPublished - 2021 Jun


  • Activation of fas and TRAIL mediated extrinsic apoptotic pathways by IL-6
  • Enhancement of cleavage of caspase-8 and caspase-3 by IL-6
  • p53 dependent upregulation of death receptors by IL-6
  • Promotion of TNF-α, TRAIL/Apo2L dependent cell death by IL-6

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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