Document Detail


KSRP: a checkpoint for inflammatory cytokine production in astrocytes.
MedLine Citation:
PMID:  22847996     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic inflammation in the central nervous system (CNS) is a central feature of many neurodegenerative and autoimmune diseases. As an immunologically competent cell, the astrocyte plays an important role in CNS inflammation. It is capable of expressing a number of cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) that promote inflammation directly and through the recruitment of immune cells. Checkpoints are therefore in place to keep tight control over cytokine production. Adenylate/uridylate-rich elements (ARE) in the 3' untranslated region of cytokine mRNAs serve as a major checkpoint by regulating mRNA stability and translational efficiency. Here, we examined the impact of KH-type splicing regulatory protein (KSRP), an RNA binding protein which destabilizes mRNAs via the ARE, on cytokine expression and paracrine phenotypes of primary astrocytes. We identified a network of inflammatory mediators, including TNF-α and IL-1β, whose expression increased 2 to 4-fold at the RNA level in astrocytes isolated from KSRP(-/-) mice compared to littermate controls. Upon activation, KSRP(-/-) astrocytes produced TNF-α and IL-1β at levels that exceeded control cells by 15-fold or more. Conditioned media from KSRP(-/-) astrocytes induced chemotaxis and neuronal cell death in vitro. Surprisingly, we observed a prolongation of half-life in only a subset of mRNA targets and only after selective astrocyte activation. Luciferase reporter studies indicated that KSRP regulates cytokine gene expression at both transcriptional and post-transcriptional levels. Our results outline a critical role for KSRP in regulating pro-inflammatory mediators and have implications for a wide range of CNS inflammatory and autoimmune diseases.
Authors:
Xuelin Li; Wei-Jye Lin; Ching-Yi Chen; Ying Si; Xiaowen Zhang; Liang Lu; Esther Suswam; Lei Zheng; Peter H King
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-07-28
Journal Detail:
Title:  Glia     Volume:  60     ISSN:  1098-1136     ISO Abbreviation:  Glia     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-09-06     Completed Date:  2013-02-14     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  8806785     Medline TA:  Glia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1773-84     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Department of Neurology, University of Alabama, Birmingham, Alabama 35233-0017, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Astrocytes / metabolism*
Cell Death / physiology*
Cell Movement / physiology*
Cytokines / biosynthesis*
Gene Expression Regulation
Inflammation / metabolism
Interleukin-1beta / metabolism
Mice
Mice, Knockout
Neurons / metabolism
RNA-Binding Proteins / genetics,  metabolism*
Trans-Activators / genetics,  metabolism*
Tumor Necrosis Factor-alpha / metabolism
Up-Regulation
Grant Support
ID/Acronym/Agency:
CA131468/CA/NCI NIH HHS; GM068758/GM/NIGMS NIH HHS; NS057664/NS/NINDS NIH HHS; NS064133/NS/NINDS NIH HHS; R01 GM068758/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/Interleukin-1beta; 0/KSRP protein, mouse; 0/RNA-Binding Proteins; 0/Trans-Activators; 0/Tumor Necrosis Factor-alpha
Comments/Corrections

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