You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: IL-17 Attenuates Degradation of ARE-mRNAs by Changing the Cooperation between AU-Binding Proteins and microRNA16}
Article:
Abstract:
Interleukin 17A( IL-17), a mediator implicated in chronic and severe inflammatory diseases, enhances the production of pro-inflammatory mediators by attenuating decay of the encoding mRNAs. The decay of many of these mRNAs depends on proteins( AUBps) that target AU-rich elements in the 3′-untranslated region of mRNAs and facilitate either mRNA decay or stabilization. Here we show that AUBps and the target mRNA assemble in a novel ribonucleoprotein complex in the presence of microRNA16( miR16), which leads to the degradation of the target mRNA. Notably, IL-17 attenuates miR16 expression and promotes the binding of stabilizing AUBps over that of destabilizing AUBps, reducing mRNA decay. These findings indicate that miR16 independently of a seed sequence, directs the competition between degrading and stabilizing AUBps for target mRNAs. Since AUBps affect expression of about 8% of the human transcriptome and miR16 is ubiquitously expressed, IL-17 may in addition to inflammation affect many other cellular processes.
Introduction:
Interleukin-17A( IL-17), the prototype of the IL-17 cytokine family[1],[2], is a major player in the development of auto-immunity, host defence and inflammation[3]. IL-17 acts as a homodimeric molecule, although it can form heterodimers with IL-17F[2], and predominantly activates stromal cells via the receptors IL-17RA and IL-17RC[4]. IL-17 by itself, but most markedly in synergy with pro-inflammatory stimuli such as TNF-α, controls the production of pro-inflammatory mediators. IL-17 has been shown to induce gene transcription via the NFκB pathway by up-regulating IκBζ[5] and that of C/EBP by promoting transcription of C/EBP-β and C/EBP-δ[6]. IL-17 has also been shown to attenuate mRNA degradation via MAPK[7] and IKKi[8]. These transcriptional and post-transcriptional mechanisms may underlie the enhanced production of inflammatory mediators by IL-17. For lung epithelial(-like) cells we have established previously that IL-17 synergizes with the TNF-α-induced production of the pro-inflammatory mediators IL-8 and IL-6 by attenuating degradation of the respective mRNAs[9], with a weak transcriptional effect at most. The mechanism by which IL-17 attenuates mRNA degradation has remained elusive. A major mRNA decay pathway is mediated by AU-rich-elements( AREs) in the 3′-untranslated region( 3′-UTR) of mRNAs[10]. These AREs are found in 8% of the human transcripts encoding inflammatory mediators, transcription factors, proteins controlling the cell cycle, and many other classes of proteins, affecting virtually all cellular and physiological processes[11]. Although the machinery involved in this ARE-mediated mRNA decay( AMD) pathway is still far from clear, over the last 10–15 years a family of proteins has been discovered that recognizes these AREs and influence AMD. The proteins tristetraprolin( TTP)[12], AU-binding factor 1( AUF-1)[13], the ELAV-like protein HuR[14],[15], KH-type splicing regulatory protein( KHSRP)[16], T-cell intracellular antigen( TIA)-1[17] and TIA-1-related protein( TIAR)[18] are all acknowledged ARE-binding proteins. TTP, AUF-1 and KHSRP have been shown to promote mRNA degradation, HuR and also AUF-1 was shown to attenuate mRNA degradation, whereas TIA-1 and TIAR mediate translational repression. The prevailing paradigm is that the balance of the various AUBps determines the effect on the targeted mRNA[19]. More recently, small non-coding RNA molecules, called microRNAs( miRs), have been implicated in 3′-UTR-mediated mRNA degradation[20]. miRs bind a target mRNA via a seed sequence and, for animal cells, complementarity between the miR and the target mRNA promotes mRNA degradation[20]. This degradation is facilitated by catalytic argonaute proteins in the RISC complex[21]. We set out to delineate the mechanism by which the degradation of mRNAs encoding for IL-8, GM-CSF and IL-6 is regulated. These mRNAs assembled with various AUBps in a novel ribonucleoprotein complex in the presence of miR16, which lead to their decay. For example, IL-8 mRNA degradation was cooperatively promoted by TTP, KHSRP and miR16. Alternatively, IL-8 mRNA degradation was inhibited by AUF-1 in the absence of miR16. IL-17 attenuated miR16 expression and binding to the complex, and markedly promoted binding of IL-8 mRNA to AUF-1, in line with stabilization of IL-8 mRNA. Similar findings were obtained for other ARE-containing mRNAs, indicating that the various AUBps compete for binding to the target mRNA, the balance of which is regulated by IL-17, likely via miR16. This suggests that miR16 may direct competition between the AUBps and herewith the expression of proteins encoded by ARE-containing transcripts, many of which have regulatory functions that contribute to the pathophysiology of chronic inflammatory diseases[11].
Discussion:
IL-17 is associated with chronic inflammatory diseases[3] and is increasingly being linked to the severity of inflammatory diseases such as in asthma[31]. This association likely arises from the synergy between IL-17 and pro-inflammatory stimuli like TNF-α in the production of pro-inflammatory mediators, particularly by stromal cells. For epithelial and fibroblast cells, IL-17 in combination with TNF-α has been shown to predominantly attenuate degradation of mRNAs encoding inflammatory mediators[9],[32], which results in a hyper-responsive production of these pro-inflammatory mediators[9],[33],[34]. Here we report that degradation of mRNAs encoding IL-8, IL-6 and G-CSF is directed by the AMD mRNA decay pathway, which depends on the concerted action of various AUBps and, interestingly, miR16. The relative contribution of each of the AUBps studied here and that of miR16 depends on the target mRNA. Degradation of IL-8 mRNA depended particularly on the AUBps TTP and KHSRP, and miR16, whereas IL-8 mRNA stabilization depended on AUF-1. IL-17 in presence of TNF-α changed the relative contribution of the various AUBps, best exemplified by the 400-fold enhanced binding of AUF-1 to IL-8 mRNA, protecting IL-8 mRNA from degradation. IL-17 in combination with TNF-α also attenuated expression of miR16, paralleled by reduced amounts of miR16 bound to the various immuno-purified AUBps, thereby dissipating the contribution of miR16 to IL-8 mRNA degradation. The relative contributions of these AUBps and that of miR16 were different in the cases of IL-6 and G-CSF but, as with IL-8 expression, IL-17 in presence of TNF-α also changed the relative contribution of these AUBps and that of miR16. This cooperation between miR16 and various AU-containing mRNAs, and the impact of the synergistic effect of IL-17 and TNF-α, has been depicted in Fig. 7. It is likely that other AUBps not studied here, such as HuR, TIA-1 and TIAR contribute to the expression of ARE-containing mRNAs in a manner similar to TTP, KHSRP and AUF-1. The role of TIA-1 and TIAR may be particularly interesting, as they have been implicated in translational control. Along similar lines other microRNAs, particularly those that contain complementary AU-rich-sequences similar to those of miR16, may fulfil a similar role as miR16. In view of these findings it was unexpected that VEGF, which is encoded by a mRNA that also contains AU-rich elements in its 3′-UTR, was not regulated by any of the AUBps studied here. As yet, however, we cannot exclude the involvement of other AUBps. VEGF expression was controlled by miR16 at all conditions tested and most dependent in cells exposed to TNF-α plus IL-17( Fig. 6f), which may relate to the IL-17-reduced miR16 levels in these cells. Interestingly, VEGF mRNA contains the seed sequence for miR16, but is not clear whether that determines the apparent independency of AUBps. Datta and colleagues[35] have found that the IL-17 regulated stability of CXCL1 mRNA was also independent of the existing AU-rich elements. In a follow-up study by this group[36] it was shown that IL-17 stabilized CXCL1 mRNA and several other mRNAs via TRAF5 and the splicing regulatory factor, SF2, which binds to 3′-UTR of CXCL1 mRNA, analogous to that reported for AUBps to the ARE sequences in the 3′-UTR of mRNAs. These findings likely relate to the notion that not all AU-rich elements are functional[37]. Jing and colleagues[30] have proposed that miR16 assists TTP in binding to its target TNF-α mRNA, possibly by the complementary sequences between miR16 and the AU-rich elements in TNF-α mRNA. Our data indicate that mRNA and miR16 indeed can complex with TTP, or KHSRP instead, but this association varies with conditions to which cells were exposed( unstimulated versus TNF-α versus TNF-α plus IL-17). In the presence of TNF-α plus IL-17, TTP and KHSRP were associated with target mRNAs in the absence of miR16. AUF-1 did not co-purify with miR16 at any of the conditions. So, it appears that miR16 is not required for binding of AUBps and their target mRNA. Its correlation with mRNA decay, however, suggests that miR16 may promote ARE-mediated mRNA degradation, in particular by KHSRP and TTP. IL-17 induced inhibition of miR16 expression as well as inhibition of miR16 using complementary LNA, resulted in an attenuated mRNA degradation. We have attempted to enhance miR16 expression by stable transfection and transduction with lentiviral constructs expressing miR16( collaboration with InteRNA, Utrecht, The Netherlands) to determine whether that would promote mRNA degradation. Whereas other miR's were over-expressed by transduction with lentiviral constructs, we have not been able to enhance miR16 levels by stable transfection and transduction with lentiviral constructs expressing miR16, suggesting that miR16 expression may be strictly controlled. Our data also show that with reduced amounts of miR16 the stabilizing AUF-1 can outcompete TTP and KHSRP for binding to IL-8 mRNA and halt its degradation. The absence of a seed sequence for miR16 in IL-8 mRNA and other mRNAs indicate that miR16 may indeed interact by complementarity to the AU-rich elements, but other modes of interaction such as suggested recently[38] are not excluded. Our methodology for purifying these complexes was aimed at preventing non-specific interactions, by meticulously eluting the AUBps using aspecific antibodies as well as a high and low salt elution steps. We have started to analyze the proteins within the complex where the presence of poly-A tail-binding protein( PABP) and ribosomal proteins( L5, S8, S19) suggest that this complex is close to that which promotes translation. This is supported by the observed correlations between the amount of target mRNA and the translated protein. As yet we have not found proteins that are part of the RISC complex. Overall our data indicate that the interactions between AUBps, miR16 and the target mRNA largely depends on the specific RNA sequences and probably structural restraints. IL-17 exerts its function by changing the contribution of miR16 and AUBps. Besides IL-17, IL-1β has also been shown to attenuate mRNA degradation[9],[39]. As IL-17 did not synergize with IL-1β-induced IL-8 and IL-6 production by airway epithelial cells[9], it is likely that IL-1β uses the same mode of regulation as IL-17[39]. The link between the AMD pathway and IL-17 is intriguing. The AMD pathway regulates the expression of 8% of the human transcriptome, comprising mRNAs encoding proteins that regulate a range of cellular and physiological processes. This implies that IL-17 may contribute to the pathophysiology of inflammatory diseases not only by enhancing the production of inflammatory mediators, but also by promoting the production of other regulatory proteins, which may affect processes such as tissue repair and cell cycling. If so, this underlines the relevance of targeting IL-17 in inflammatory conditions.
Inflammation is driven by inflammatory mediators . Interleukin 17A ( IL-17 ) is implicated in chronic and severe inflammation and exaggerates production of inflammatory mediators . This is due , at least in part , to the IL-17-attenuated degradation of mRNAs encoding these inflammatory mediators , but the underlying mechanism has remained elusive . Most of these mRNAs contain AU-rich elements in their 3′-untranslated region and are targeted by AU-binding proteins ( AUBps ) that promote either mRNA degradation or stabilization . Here we show that IL-17 directs the AU-mediated mRNA degradation ( AMD pathway ) by modulating the interaction of degrading and stabilizing AUBps via microRNA16 ( miR16 ) . Whereas microRNAs target mRNAs to the RISC pathway for degradation by binding to a seed sequence , miR16 drives degradation by the AMD pathway without an apparent seed sequence . Transcriptome analyses have revealed that the expression of 8% of all eukaryotic transcripts is dependent on the AMD pathway . Therefore , the impact of IL-17 on inflammatory diseases may extend beyond the production of inflammatory mediators to processes like tissue repair , cell cycle , etc . In addition , targeting AUBp and/or miR16 may provide a novel therapeutic option to combat the IL-17 axis of inflammation .