Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Abstract

Inflammatory gene expression is controlled by post-transcriptional mechanisms. Many relevant transcripts contain AU-rich elements (AREs) 4 that can impose rapid degradation and restrict translation (1-3). Several proteins that interact with and mediate the effects of AREs have been identified. One of them, heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) is a member of the far upstream sequence element-binding proteins (4). It is a single-stranded nucleic acid-binding protein that contains four KH domains and has been reported to participate in transcription as well as splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (for a review, see Ref. 5). Most recently it has been found to contribute to regulation of RNA 3Ј-end processing (6).KSRP has been shown to facilitate mRNA degradation by directly binding to AREs and recruiting mRNA-degrading enzymes (7,8). Ksrp Ϫ/Ϫ cells and mice produce more type I interferons as a result of decreased mRNA decay and are refractory to viral infection (9). Different conditions of cellular activation or differentiation have been described to reduce KSRP binding and increase stability of specific mRNAs (e.g. Refs. 10 -13). The proinflammatory cytokine IL-1 can induce stabilization of KSRP target mRNAs, including that of IL-6 (14, 15), by reducing interaction of KSRP with the ARE presumably as a result of KSRP phosphorylation by p38 MAP kinase (10).IL-6, originally cloned as 26-kDa protein (16), IFN-␤2 (17), and BSF-2 (18), is a pleiotropic cytokine with important roles in inflammation, immune regulation, oncogenesis, and other physiological and pathological processes. Accordingly, interfering with IL-6 action is the aim of therapeutic strategies (19,20). IL-6 is induced in various cell types by a plethora of activators. Among the strongest and first identified are the proinflammatory cytokines tumor necrosis factor (TNF) (21) and IL-1 (22). Expression of IL-6 is controlled by transcriptional and post-transcriptional mechanisms. The latter involve AREs and a putative stem-loop structure that cause rapid degradation of the mRNA (23). Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (14, 24). IL-6 expression is also controlled by miRNAs (25,26).Our recent data showed that, in addition to stabilizing mRNAs, IL-1 can activate translation of mRNAs, including that of . We now provide evidence that repressed basal translation of IL-6 and a group of other mRNAs depends on KSRP. Interaction of KSRP with the IL-6 ARE is direct and is decreased in response to IL-1, suggesting a novel, miRNA-independent function for KSRP in translation.

Interleukin-17 (IL-17) and IL-1 Activate Translation of Overlapping Sets of mRNAs, Including That of the Negative Regulator of Inflammation, MCPIP1

“…A number of studies including our own have demonstrated that IL-1, a central mediator of inflammation, can induce stabilization of certain mRNAs, which encode proteins involved in inflammatory and immune reactions. More recently, we observed that IL-1 also activates translation of distinct mRNAs (2,3). We now present evidence that translation of several of its target mRNAs is also activated by the proinflammatory cytokine IL-17.…”

“…Although several pathways, including NF-B and MAP kinase pathways, appear to contribute to transcriptional activation, it is well established that part of the effects of IL-17 on gene expression is caused by stabilization of mRNAs (12,13). Stabilization of cyclooxygenase-2 mRNA was found to depend on p38 MAP kinase (14), whereas CXCL1 (KC) mRNA was stabilized independently of p38 MAP kinase and of AU-rich elements (AREs) 3 (15,16), through a mechanism that, according to most recent evidence, involves inducible IB kinase, TRAF5, and SF2 (17,18). In this study, we provide evidence that IL-17 can induce proteins by activating translation of distinct target mRNAs, including those of IB and MCPIP1.…”

Enterovirus 71 Infection Cleaves a Negative Regulator for Viral Internal Ribosomal Entry Site-Driven Translation

“…6). This datum may help further our understanding of the molecular functions of FBP2, which is molecularly significant for translation (35,61), RNA stability (41,42), and miRNA biogenesis (43)(44)(45).…”

AU-Rich-Element-Dependent Translation Repression Requires the Cooperation of Tristetraprolin and RCK/P54

“…In addition, AUF1 and TIAR control translation of MYC mRNA (32). Recently, the ELAV protein HuD and KSRP were implicated in ARE-mRNA translational regulation (14,19).…”