The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 261K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Friedlander, R. M.
Right arrow Articles by Yuan, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Friedlander, R. M.
Right arrow Articles by Yuan, J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
© The Rockefeller University Press, 0022-1007/1997/3/933/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 5, March 3, 1997 933-940

Articles

Expression of a Dominant Negative Mutant of Interleukin-1β Converting Enzyme in Transgenic Mice Prevents Neuronal Cell Death Induced by Trophic Factor Withdrawal and Ischemic Brain Injury

Robert M. Friedlander*,{ddagger}, Valeria Gagliardini*, Hideaki Hara§, Klaus B. Fink§, Weiwei Li*, Glen MacDonald||, Mark C. Fishman*, Arnold H. Greenberg||, Michael A. Moskowitz§, and Junying Yuan*

From the * Cardiovascular Research Center, Department of Medicine, {ddagger} Neurosurgical Service, Department of Surgery, and § Stroke and Neurovascular Regulation, Neurosurgical Service, Department of Surgery, and Neurology Department, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129; and the || Manitoba Institute of Cell Biology, Manitoba Cancer Treatment and Research Foundation, University of Manitoba, Winnipeg, Manitoba R3EOV9, Canada

To explore the role of the interleukin (IL)-1β converting enzyme (ICE) in neuronal apoptosis, we designed a mutant ICE gene (C285G) that acts as a dominant negative ICE inhibitor. Microinjection of the mutant ICE gene into embryonal chicken dorsal root ganglial neurons inhibits trophic factor withdrawal–induced apoptosis. Transgenic mice expressing the fused mutant ICE-lacZ gene under the control of the neuron specific enolase promoter appeared neurologically normal. These mice are deficient in processing pro–IL-1β, indicating that mutant ICEC285G blocks ICE function. Dorsal root ganglial neurons isolated from transgenic mice were resistant to trophic factor withdrawal–induced apoptosis. In addition, the neurons isolated from newborn ICE knockout mice are similarly resistant to trophic factor withdrawal–induced apoptosis. After permanent focal ischemia by middle cerebral artery occlusion, the mutant ICEC285G transgenic mice show significantly reduced brain injury as well as less behavioral deficits when compared to the wild-type controls. Since ICE is the only enzyme with IL-1β convertase activity in mice, our data indicates that the mutant ICEC285G inhibits ICE, and hence mature IL-1β production, and through this mechanism, at least in part, inhibits apoptosis. Our data suggest that genetic manipulation using ICE family dominant negative inhibitors can ameliorate the extent of ischemia-induced brain injury and preserve neurological function.

Address correspondence to Junying Yuan, Department of Cell Biology, 240 Longwood Ave., Harvard Medical School, Boston, MA 02115.

J. Yuan was supported in part by grants from the National Institute of Aging, National Institute of Neurological Disorders and Stroke, and Bristol Myer-Squibb. R.M. Friedlander was supported by a postdoctoral training fellowship from National Institutes of Health and by an Upjohn sponsored award from the Joint Section on Cerebrovascular Surgery (Congress of Neurological Surgeons and the American Association of Neurological Surgeons) and from American Brain Tumor Association. M.A. Moskowitz, H. Hara, and K.B. Fink were supported by a grant from the National Institute of Neurological Disorders Interdepartmental Stroke Program Project (NS10828). K.B. Fink was supported by the Deutsche Forschungs Gemelnschaft (F:600/2-1). M.C. Fishman and W. Li were supported by a grant from Bristol Myer-Squibb. A.H. Greenberg and G. MacDonald were supported by a grant from the National Cancer Institute of Canada and the Medical Research Council of Canada.

1Abbreviations used in this paper: DRG, dorsal root ganglion; ICE, IL-1β converting enzyme; MCA, middle cerebral artery; NGF, nerve growth factor; NSE, neuron specific enolase.

R. Friedlander and V. Gagliardini contributed equally to this work.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS