Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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The Role of Uteroglobin in the Immunomodulation of Nonsmall Cell Lung Cancer Cells

비소세포 폐암세포에서 Uteroglobin의 면역 조절 기능에 대한 연구

  • Yoon, Jung Min (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University, College of Medicine) ;
  • Lim, Jae-Jun (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University, College of Medicine) ;
  • Yoo, Chul-Gyu (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University, College of Medicine) ;
  • Lee, Choon-Taek (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University, College of Medicine) ;
  • Han, Sung Koo (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University, College of Medicine) ;
  • Shim, Young-Soo (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University, College of Medicine) ;
  • Kim, Young Whan (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University, College of Medicine)
  • 윤정민 (서울대학교 의과대학 내과학교실 및 의학연구원 폐 연구소) ;
  • 임재준 (서울대학교 의과대학 내과학교실 및 의학연구원 폐 연구소) ;
  • 유철규 (서울대학교 의과대학 내과학교실 및 의학연구원 폐 연구소) ;
  • 이춘택 (서울대학교 의과대학 내과학교실 및 의학연구원 폐 연구소) ;
  • 한성구 (서울대학교 의과대학 내과학교실 및 의학연구원 폐 연구소) ;
  • 심영수 (서울대학교 의과대학 내과학교실 및 의학연구원 폐 연구소) ;
  • 김영환 (서울대학교 의과대학 내과학교실 및 의학연구원 폐 연구소)
  • Received : 2004.07.28
  • Accepted : 2004.08.31
  • Published : 2004.10.30
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Abstract

Background : Immunotherapy for cancer has not been successful because of several obstacles in tumor and its environment. Inappropriate secretions of cytokines and growth factors by tumors cause substantial changes in the immune responses against tumors, affording the tumors some degree of protection from immune attack. Uteroglobin (UG, Clara cell secretory protein) has been known to have anti-inflammatory, immunomodulatory and anti-cancer activities. However, in lung cancer cells, UG expression is decreased. This study investigated the role of UG in the immunomodulation of lung cancer. Methods : The UG protein was overexpressed by Adenovirus(Ad)-UG transduction in non-small cell lung cancer cell lines. The concentration of Prostaglandin $E_2$ ($PGE_2$) was measured by Enzyme Immunoassay (EIA). Peripheral blood mononuclear cells (PBMC) from whole blood were prepared with Ficoll. PBMC were cultured in RPMI 1640, supernatant of A549, or A549 with UG or NS-398. Concentration of Th 1 type and Th 2 type cytokines from PBMC were measured by ELISA. Results : UG suppressed $PGE_2$, Cyclooxygenase-2 (COX-2) product. Both Th1 type such as Interleukin-2 (IL-2), Interferon-${\gamma}$ (IFN-${\gamma}$) and Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and Th2 type cytokines such as IL-10 and Tumor growth factor-${\beta}$ (TGF-${\beta}$) were increased when PBMC were cultured with supernatant of non small lung cancer cells. UG and COX-2 inhibitor, NS-398 induced normal immune response of PBMC. Although Th 1 type cytokines were increased, Th 2 type cytokines were reduced by UG. Conclusion : UG suppressed PGE2, COX-2 product. Supernatant of NSCLC induced imbalance of immune response of PBMC. However, UG reversed this imbalance. These results suggest that UG may be used in the development of immunotherapy for lung cancer.

연구배경 : 폐암에 대한 거의 대부분의 면역 치료는 실패하였는데, 이는 폐암 자체에 존재하는 면역 억제 기전을 극복하지 못한데 기인하는 것으로 판단된다. Uteroglobin (UG, CCSP)은 항염증 등의 활성을 보인다. 방 법 : A549에 Ad-UG을 처리하고, 상층액의 $PGE_2$ 농도를 측정하였다. RPMI 1640, A549 배양액과 UG 혹은 COX-2 억제제인 NS-398을 처리 후 얻은 폐암세포주 상층액으로 PBMC를 배양 후 Th 1 type cytokines과 Th 2 type cytokines의 농도를 측정하였다. 결 과 : $PGE_2$는 UG이 발현되는 세포주에서 감소하였다. 폐암 세포 배양 배지로 키운 면역 세포의 cytokines가 증가하는 양상을 보였으나, UG등을 처리한 비소세포 폐암주의 배양액은 PBMC의 면역 반응을 정상적으로 유도하였다. 결 론 : 비소세포폐암주 배양액은 PBMC의 면역 반응을 비정상적으로 유도하지만, UG은 $PGE_2$의 분비를 억제함으로써, PBMC의 면역 반응을 강화시킨다.

Keywords

References

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