Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Carbon Monoxide Inhibits PMA-induced Differentiation in Human Monocytic THP-1 Cells

단핵구세포주 THP-1의 대식세포로의 분화 및 활성화에서 CO의 억제 효과

  • Kim, Da Sol (Department of Microbiology & Immunology, Pusan National University College of Medicine) ;
  • Lee, Mi Sun (Department of Microbiology & Immunology, Pusan National University College of Medicine) ;
  • Kim, Han Sol (Department of Premedicine, Pusan National University College of Medicine) ;
  • Lee, Hye Yun (Department of Premedicine, Pusan National University College of Medicine) ;
  • Kim, Oh Yun (Department of Premedicine, Pusan National University College of Medicine) ;
  • Kang, Ye Rin (Department of Premedicine, Pusan National University College of Medicine) ;
  • Sohn, Dong Hyun (Department of Microbiology & Immunology, Pusan National University College of Medicine) ;
  • Kim, Koanhoi (Department of Pharmacology, Pusan National University College of Medicine) ;
  • Park, Young Chul (Department of Microbiology & Immunology, Pusan National University College of Medicine)
  • 김다솔 (부산대학교 의과대학 미생물학 및 면역학교실) ;
  • 이미선 (부산대학교 의과대학 미생물학 및 면역학교실) ;
  • 김한솔 (부산대학교 의과대학 의예과) ;
  • 이혜윤 (부산대학교 의과대학 의예과) ;
  • 김오윤 (부산대학교 의과대학 의예과) ;
  • 강예린 (부산대학교 의과대학 의예과) ;
  • 손동현 (부산대학교 의과대학 미생물학 및 면역학교실) ;
  • 김관회 (부산대학교 의과대학 약리학교실) ;
  • 박영철 (부산대학교 의과대학 미생물학 및 면역학교실)
  • Received : 2016.11.25
  • Accepted : 2017.01.04
  • Published : 2017.02.28
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Abstract

Carbon monoxide (CO), a reaction product of cytoprotective enzyme heme oxygenase-1 (HO-1), is a gaseous messenger with anti-proliferative, anti-apoptotic, and anti-inflammatory actions in many cell types. Here, we investigated the role of CO on the process of monocyte differentiation induced by phorbol 12-myristate 13-acetate (PMA) in human monocytic THP-1 cells. CORM-2 (tricarbonyldichlororuthenium (II) dimer, $Ru2Cl_4(CO)_6$), a CO-releasing compound, decreased a marked cell adherence with a slight reduction of proliferation in monocytic THP-1 cells treated with PMA. And, CORM-2 significantly inhibited expression of differentiation markers such as CD14, CD11b plus CD18 (macrophage-1 antigen, Mac-1 or complement receptor 3, CR3) and phagocytosis of carboxylate-modified red fluorescent latex beads, in PMA-stimulated THP-1 cells. For the further experiments, differentiation of PMA-treated cells was enhanced after the initial 2 days stimulus by removing the PMA-containing media then incubating the cells in fresh media for a another 4 days. And, we observed the secretion of inflammatory cytokines and phagocytosis in differentiated macrophages. Treatment with CORM-2 significantly abolished the secretion of IL-6, $TNF-{\alpha}$ and phagocytosis using fluorescence-conjugated E. coli (K-12 strain) bioparticles in lipopolysaccharide (LPS)-stimulated differentiated macrophages. In conclusion, these results suggest that CO inhibits the differentiation of monocytic THP-1 cells as well as the activation of differentiated macrophages.

Carbon monoxide (CO)는 세포 보호의 기능을 가지는 항산화 효소인 heme oxygenase-1 (HO-1)의 대사산물로 세포성장, 아폽토시스, 염증에 대한 억제 효과를 보이는 것으로 보고가 이어지고 있고, 이에 관련된 연구가 활발히 진행되고 있는 실정이다. 본 연구에서는 CO가 단핵구의 대식세포로의 분화 및 그 활성화 과정에 미치는 영향을 인간 단핵구세포주 THP-1을 이용하여 조사하였다. CO-releasing compound인 CORM-2는 phorbol 12-myristate 13-acetate (PMA)로 자극한 THP-1 세포에서 viability와 증식에는 큰 영향을 주지 않았으나 부착능의 뚜렷한 감소를 보였다. 그리고, CORM-2는 대식세포의 막표면 분화 인자인 CD14, CD11b 및 CD18의 발현과 latex beads를 이용한 포식 기능을 현저히 억제하였다. 다음으로, 배양중인 THP-1 세포를 PMA로 6일 동안 대식세포로 분화시킨 후 inflammatory cytokines의 분비와 포식 기능을 조사하였다. CORM-2의 처리는 lipopolysaccaride (LPS)로 자극한 대식세포로부터 분비되는 IL-6와 $TNF-{\alpha}$의 분비를 감소시켰다. 또한, 분화된 대식세포에 E. coli (K-12 strain) bioparticles를 이용하여 포식 기능을 측정한 결과 CORM-2를 처리한 세포에서는 현저히 감소되는 경향을 보였다. 이를 종합해 볼 때, CO는 항원 인식과 포식 기능에 관여하는 막단백질의 발현을 저해함으로써 단핵구의 분화과정을 억제하였고, 분화된 대식세포의 inflammatory cytokines의 분비 및 포식 기능을 저해함으로써 활성화 과정도 억제하는 것으로 보인다.

Keywords

References

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