Extracellular Nampt Promotes Macrophage Survival via a Nonenzymatic Interleukin-6/STAT3 Signaling Mechanism*
- Yankun Li‡,1,
- Yuan Zhang‡,1,
- Bernhard Dorweiler‡§,
- Dongying Cui‡,
- Tao Wang¶,
- Connie W. Woo‡,
- Cynthia S. Brunkan∥,
- Cynthia Wolberger¶,
- Shin-ichiro Imai∥ and
- Ira Tabas‡,**,‡‡,2
- Departments of ‡Medicine, **Pathology and Cell Biology, and ‡‡Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, the §Department of Cardiothoracic and Vascular Surgery, University Hospital, University of Mainz, Mainz, Germany, the ¶Department of Biophysics and Biophysical Chemistry and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185, and the ∥Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110
- ↵2 To whom correspondence should be addressed: Dept. of Medicine, Columbia University, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-9430; Fax: 212-305-4834; E-mail: iat1@columbia.edu.
Abstract
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.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grants R01 HL075662 and P01 HL087123 (to I. T.) and National Institutes of Health, NIA, Grant AG024150. This work was also supported by United States Army Medical Research and Materiel Command (USAMRMC) Grant W81XWH-06-1-0212 (to I. T.); grants from the Glenn Foundation, Ellison Medical Foundation, American Diabetes Association, and Juvenile Diabetes Research Foundation (to S. I.); and Deutsche Forschungsgemeinschaft Grant DO1289/2-1 (to B. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Present address: Cardiovascular Disease, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
- Received July 30, 2008.
- Revision received October 7, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
