title: KSRP: a checkpoint for inflammatory cytokine production in astrocytes.
abstract: 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: Department of Neurology, University of Alabama, Birmingham, Alabama 35233-0017, USA.
authors: Xuelin
authors: X
authors: Li
authors: Wei-Jye
authors: WJ
authors: Lin
authors: Ching-Yi
authors: CY
authors: Chen
authors: Ying
authors: Y
authors: Si
authors: Xiaowen
authors: X
authors: Zhang
authors: Liang
authors: L
authors: Lu
authors: Esther
authors: E
authors: Suswam
authors: Lei
authors: L
authors: Zheng
authors: Peter H
authors: PH
authors: King
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; C507913:Khsrp protein, mouse; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha