Molt-4 T세포에 있어서 Mycophenolic Acid에 의한 세포고사의 신호전달 기전
Mycophenolic Acid Induced Apoptotic Signal Transduction in Molt-4 T-cells
최수진나, 정상영, 김신곤,
소속 상세정보
최수진나 ( Choi Soo-Jin-Na )
전남대학교 의과대학 외과학교실
정상영 ( Chung Sang-Young )
전남대학교 의과대학 외과학교실
김신곤 ( Kim Shin-Kon )
전남대학교 의과대학 외과학교실
KMID : 0371320020620010008
Abstract
Purpose : Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), is the active metabolite of the immunosuppressive drug, mycophenolate mofetil (MMF). MMF is used to prevent an immunemediate rejection
response following organ transplantation via the inhibition of the IMPDH and GTP biosynthesis pathway. This study was designed to elucidate the mechanism by which MPA exerts its cytotoxic effect on human T lymphocytic and monocytic cell lines.
Methods : MOLT-4 and U937 cell lines were treated with MPA. Cell viability, expression of Bcl2 family proteins and Fas/Fas-L, effects of antioxidants and intracellular Ca2+ regulating agents and apoptosis were
measured
using
a variety of microscopic and biochemical techniques.
Results : MPA induced the death of U937 and MOLT-4 cells in dose and time dependent manners, which was revealed an apoptosis with a characteristic ladder pattern of DNA fragmentation. In addition, BAPTA/AM, an intracellular Ca2+
chelator protected MOLT-4 cells from MPA treated apoptosis, although it did not have an additive with thapsigargin, and increases cytosolic Ca2+ stores. However, antioxidants including reduced glutathione (GSH) and N-acetyl-L-cysteine
(NAC)
did not inhibit the apoptosis of cells by MPA. Furthermore, guanosine suppressed MPA induced apoptosis of MOLT-4 lymphocytes, although adenosine did not. MPA also increased the catalytic activity of caspase family cysteine proteases including
caspase-8,
9 and 3 proteases in MOLT-4 cells. Sequential activation indicated that the cleavage of caspase-8 and 9 precedes those of caspase-3.
Conclusion : The results suggest that MPA induces the apoptotic death of MOLT-4 lymphocytes via the activations of caspase family proteases and the depletion of GTP.
키워드
Mycophenolic acid; 세포고사; Bcl2 family 단백질; Caspase family cysteine proteases; GTP; Mycophenolic acid; Apoptosis; Bcl2 family proteins; Caspase family cysteine proteases; GTP;
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