| First Author | Li X | Year | 2012 |
| Journal | Glia | Volume | 60 |
| Issue | 11 | Pages | 1773-84 |
| PubMed ID | 22847996 | Mgi Jnum | J:187384 |
| Mgi Id | MGI:5436343 | Doi | 10.1002/glia.22396 |
| Citation | Li X, et al. (2012) KSRP: A checkpoint for inflammatory cytokine production in astrocytes. Glia 60(11):1773-84 |
| abstractText | 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-alpha) and interleukin-1 beta (IL-1beta) 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-alpha and IL-1beta, 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-alpha and IL-1beta 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. (c) 2012 Wiley Periodicals, Inc. |
