TNF Receptors Differentially Signal and Are Differentially Expressed and Regulated in the Human Heart

被引:43
作者
Al-Lamki, R. S. [1 ]
Brookes, A. P. [1 ]
Wang, J. [1 ]
Reid, M. J. [1 ]
Parameshwar, J. [2 ]
Goddard, M. J. [3 ]
Tellides, G. [4 ]
Wan, T. [5 ]
Min, W. [5 ]
Pober, J. S. [6 ]
Bradley, J. R. [1 ]
机构
[1] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 1TN, England
[2] Papworth Hosp, Dept Transplantat, Cambridge CB3 8RE, England
[3] Papworth Hosp, Dept Pathol, Cambridge CB3 8RE, England
[4] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA
[5] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA
[6] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06510 USA
基金
美国国家卫生研究院;
关键词
Apoptosis; cardiomyocytes; cell cycle entry; TNF; TNFR1; TNFR2; TUMOR-NECROSIS-FACTOR; INFLAMMATORY-BOWEL-DISEASE; ALPHA CONVERTING-ENZYME; CARDIAC MYOCYTES; MYOCARDIAL-INFARCTION; INDUCED APOPTOSIS; CELL; REJECTION; FAILURE; TRANSPLANTATION;
D O I
10.1111/j.1600-6143.2009.02831.x
中图分类号
R61 [外科手术学];
学科分类号
摘要
Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wildtype ((WT)C57BL/6), TNFR1-knockout ((KO)), TNFR2(KO), TNFR1/2(KO) mice. In nonrejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co-expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In WTC57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1(KO) myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2(KO) myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2-mediated repair.
引用
收藏
页码:2679 / 2696
页数:18
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