Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival

被引:128
作者
Liu, HT
Ma, YY
Cole, SM
Zander, C
Chen, KH
Karras, J
Pope, RM
机构
[1] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Rheumatol, Chicago, IL 60611 USA
[2] Cathay Gen Hosp, Taipei, Taiwan
[3] ISIS Pharmaceut, Carlsbad, CA 92008 USA
关键词
D O I
10.1182/blood-2002-11-3396
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The Bcl-2 family member Mcl-1 is essential for macrophage survival. However, the mechanisms that contribute to the expression of Mcl-1 in these cells have not been fully characterized. The present study focused on the role of signal transducer and activator of transcription 3 (STAT3) in regulation of Mcl-1 in macrophages. Sodium salicylate (NaSal) treatment induced apoptotic cell death in primary human macrophages in a dose- and time-dependent fashion. Incubation with NaSal resulted in the loss of mitochondrial transmembrane potential, the release of cytochrome c and second mitochondria-derived activator of caspase/direct IAP binding protein with low pH of isoelectric point (pl) from the mitochondria, and the activation of caspases 9 and 3. Western blot analysis and reverse transcription-polymerase chain reaction demonstrated that NaSal down-regulated the expression of Mcl-1. Electrophoretic mobility shift assay and Western blot analysis for phosphorylated STAT3 demonstrated that STAT3 was constitutively activated in macrophages and that this STAT3 activation was suppressed by NaSal. The activation of STAT3 in macrophages was dependent on Ser 727 phosphorylation, in the absence of detectable Tyr(705) phosphorylation. Ectopic expression of STAT3 in murine RAW264.7 macrophages rescued the inhibition of Mcl-1 promoter-reporter gene activation and the cell death induced by NaSal treatment, while a dominant-negative STAT3 resulted in cell death. To confirm its role in primary macrophages, STAT3 antisense (AS) oligodeoxynucleotides (ODNs) were employed. STAT3 AS, but not control, ODNs decreased STAT3 and Mcl-1 expression and resulted in macrophage apoptosis. These observations demonstrate that the STAT3-mediated expression of Mcl-1 is essential for the survival of primary human in vitro differentiated macrophages. (C) 2003 by The American Society of Hematology.
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收藏
页码:344 / 352
页数:9
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