Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Auranofin Downregulates Nuclear Factor-κB Activation via Nrf2-Independent Mechanism

오라노핀에 의한 nuclear factor κB 활성저해는 Nrf2 활성화와 무관한 기전에 의함

  • Kim, Nam-Hoon (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Park, Hyo-Jung (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Kim, In-Sook (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea)
  • 김남훈 (가톨릭대학교 의과대학 의생명과학교실) ;
  • 박효정 (가톨릭대학교 의과대학 의생명과학교실) ;
  • 김인숙 (가톨릭대학교 의과대학 의생명과학교실)
  • Received : 2010.09.27
  • Accepted : 2010.12.02
  • Published : 2010.12.30
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Abstract

Transcription factors Nrf2 and NF-${\kappa}B$ are important regulators of the innate immune response, and their cross-talks in inflammation have been reported. Previously, we demonstrated that gold(I)-compound auranofin, an inhibitor of NF-${\kappa}B$ signal, induced Nrf2 activation in human synovial cells and monocytic cells. To investigate whether the Nrf2 activation is involved in the mechanism of the auranofin-attenuated NF-${\kappa}B$ signaling, we examined the effects of Nrf2 knockdown on NF-${\kappa}B$ activation using rheumatic synovial cells. When the cells were transfected with a specific siRNA for Nrf2, the gene expression was perfectly blocked. However, the Nrf2 knockdown did not cancel the suppressive effect of auranofin on TNF-$\alpha$-induced $I{\kappa}B-{\alpha}$ degradation. Treatment with a specific siRNA for HO-1, which is a target of Nrf2 and plays a role in anti-inflammation, also did not affect the blocking activity of auranofin on $I{\kappa}B-{\alpha}$ degradation. In addition, auranofin-inhibited ICAM-1 expression was not restored by Nrf2 knockdown. These findings indicate that the activated Nrf2 and HO-1 are not associated with the suppressive action of auranofin on the pro-inflammatory cytokines-stimulated NF-${\kappa}B$ activation. This suggests that Nrf2/HO-1 and NF-${\kappa}B$ signals, which are regulated by auranofin, participate in the anti-inflammatory action of auranofin via independent pathways in rheumatic synovial cells.

내재면역반응의 중요한 조절자인 Nrf2와 NF-${\kappa}B$는 염증시에 교차 작용을 통하여 서로의 전사활성을 조절할 수 있다고 보고된 바 있으나 상반된 결과도 제시되고 있어서 아직까지 확실하게 규명되어 있지 않다. 저자들은 선행연구에서 NF-${\kappa}B$ 저해제인 금(I)-화합물 오라노핀이 인간 관절활막세포와 단핵구성 세포에서 Nrf2를 활성화시킴을 확인한 바 있기 때문에, 본 연구에서는 Nrf2를 knockdown 시킨 류마티스성 활막세포를 사용하여 오라노핀에 의해 저해되는 NF-${\kappa}B$ 신호전달 과정에 Nrf2가 관여하는지를 조사하였다. 세포를 Nrf2 siRNA로 transfection시켰을 때 Nrf2 발현은 대부분 차단됨을 확인하였다. 하지만 Nrf2 knockdown은 TNF-$\alpha$에 의해 유도되는 $I{\kappa}B-{\alpha}$ 분해를 막는 오라노핀의 작용에는 영향을 주지 않았다. Nrf2 target 단백질로서 항염 작용에 관여하는 HO-1을 knockdown 시켰을 경우에도 $I{\kappa}B-{\alpha}$ 분해를 저해하는 오라노핀의 작용에 영향을 미치지 않았다. 또한, Nrf2 knockdown은 오라노핀에 의해 저해된 ICAM-1 발현을 다시 복원시키지 못했다. 이러한 결과들은 염증성 싸이토킨에 의해 유도되는 NF-${\kappa}B$ 활성화를 오라노핀이 저해하는 기전에 Nrf2 및 HO-1이 관련되어 있지 않음을 시사한다. 따라서 류마티스성 관절활막세포에서 오라노핀의 항염작용 기전으로 알려진 Nrf2/HO-1 활성유도와 NF-${\kappa}B$ 활성저해는 교차작용 없이 각각 독립적인 기전을 통해 나타나는 것으로 생각된다.

Keywords

References

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