Extracellular Nampt Promotes Macrophage Survival via a Nonenzymatic Interleukin-6/STAT3 Signaling Mechanism

被引:172
作者
Li, Yankun [1 ]
Zhang, Yuan [1 ]
Dorweiler, Bernhard [1 ,4 ]
Cui, Dongying [1 ]
Wang, Tao [5 ,6 ]
Woo, Connie W. [1 ]
Brunkan, Cynthia S. [7 ]
Wolberger, Cynthia [5 ,6 ]
Imai, Shin-ichiro [7 ]
Tabas, Ira [1 ,2 ,3 ]
机构
[1] Columbia Univ, Dept Med, New York, NY 10032 USA
[2] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA
[3] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA
[4] Johannes Gutenberg Univ Mainz, Univ Hosp, Dept Cardiothorac & Vasc Surg, Mainz, Germany
[5] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA
[6] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA
[7] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1074/jbc.M805866200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Macrophages play key roles in obesity-associated pathophysiology, including inflammation, atherosclerosis, and cancer, and processes that affect the survival-death balance of macrophages may have an important impact on obesity-related diseases. Adipocytes and other cells secrete a protein called extracellular nicotinamide phosphoribosyltransferase (eNampt; also known as pre-B cell colony enhancing factor or visfatin), and plasma levels of eNampt increase in obesity. Herein we tested the hypothesis that eNampt could promote cell survival in macrophages subjected to endoplasmic reticulum ( ER) stress, a process associated with obesity and obesity-associated diseases. We show that eNampt potently blocks macrophage apoptosis induced by a number of ER stressors. The mechanism involves a two-step sequential process: rapid induction of interleukin 6 (IL-6) secretion, followed by IL-6-mediated autocrine/paracrine activation of the prosurvival signal transducer STAT3. The ability of eNampt to trigger this IL-6/STAT3 cell survival pathway did not depend on the presence of the Nampt enzymatic substrate nicotinamide in the medium, could not be mimicked by the Nampt enzymatic product nicotinamide mononucleotide (NMN), was not blocked by the Nampt enzyme inhibitor FK866, and showed no correlation with enzyme activity in a series of site-directed mutant Nampt proteins. Thus, eNampt protects macrophages from ER stress-induced apoptosis by activating an IL-6/STAT3 signaling pathway via a nonenzymatic mechanism. These data suggest a novel action and mechanism of eNampt that could affect the balance of macrophage survival and death in the setting of obesity, which in turn could play important roles in obesity-associated diseases.
引用
收藏
页码:34833 / 34843
页数:11
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