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Originally published online as doi:10.1189/jlb.1206754 on April 4, 2007

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(Journal of Leukocyte Biology. 2007;82:213-219.)
© 2007 by Society for Leukocyte Biology

Chemokine and chemoattractant receptor expression: post-transcriptional regulation

Thomas A. Hamilton1, Michael Novotny, Shyamasree Datta, Palash Mandal, Justin Hartupee, Julie Tebo and Xiaoxia Li

Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

1 Correspondence: Department of Immunology, NE40, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA. E-mail: hamiltt{at}ccf.org

ABSTRACT

The magnitude and character of the inflammatory process are determined in part via the trafficking of leukocytes into sites of injury and infection, and this process depends on proper control of the expression of genes encoding chemoattractant peptides and their receptors. Although these controls operate at multiple mechanistic levels, recent evidence indicates that post-transcriptional events governing the half-life of select mRNAs are important determinants. Adenine-uridine rich elements (AREs) located within 3' untranslated regions (UTRs) confer constitutive mRNA instability and in some cases, stabilization following stimulation by ligands of the Toll-IL-1 receptor (TIR) family. Although the importance of AREs in determining activity and mRNA half-life is well-recognized, the mechanistic scope and diversity remain poorly understood. Using the mouse KC or CXCL1 gene as a model, we have demonstrated that the abundance of mRNA and protein produced during an inflammatory response depends on multiple mechanistically distinct AREs present in the 3' UTR of the mRNA. The mRNA encoding the receptor for N-terminal formyl-methionine-containing peptides is also unstable and subject to stabilization in response to TIR ligands. These two models can, however, be readily distinguished from one another on the basis of specific stimulus sensitivity and the signaling pathways, through which such stimuli couple to the control of mRNA decay. These models demonstrate the substantial diversity operative in the post-transcriptional regulation of inflammatory gene expression.

Key Words: mRNA stability • gene expression • inflammation

INTRODUCTION

Inflammation is a necessary response to injury and infection and depends, in many cases, on the trafficking of inflammatory leukocytes to appropriate anatomic locations [1 2 3 ]. This process is regulated by chemoattractants of endogenous and exogenous origin and the receptors through which they mediate their activity [1 , 2 ]. Although the function of endogenous chemokines and chemoattractant receptors is dependent on a variety of variables, the expression of the genes encoding them is certainly an important determinant [3 ]. The molecular basis for control of inflammatory gene expression has been studied intensely in recent years, and the evidence demonstrates that regulation operates at multiple mechanistic levels including gene transcription and mRNA metabolism [4 5 6 ].

Inflammation and associated host defense responses have significant potential for tissue damage and hence, are necessarily transient in nature, requiring a rapid induction and rapid termination [4 ]. Mechanisms for regulating the induction of gene expression through enhancing transcriptional initiation are well recognized and clearly necessary for essentially all rapid increases in inflammatory gene expression [5 6 7 ]. It is, however, equally important to regulate the process by which gene transcripts and particularly mature mRNAs are depleted from the system [8 9 10 11 ]. Indeed, many genes that contribute to the control and implementation of innate immune inflammatory responses are known to be highly unstable, exhibiting half-lives of 60 min or less [12 , 13 ]. Such short half-lives are important to ensure that gene products with the potential to promote inflammation (such as chemokines and their receptors) do not accumulate inappropriately and are eliminated upon resolution of the challenge. The message instability, however, can markedly reduce the rapid induction of these mediators [10 , 11 , 14 15 16 ], and inflammatory stimuli often engage signaling mechanisms that result in the transient stabilization of such mRNAs. Therefore, the regulation of mRNA stability is important for the induction of inflammatory gene expression as well as for its termination.

In this presentation, we will consider the mechanistic basis for mRNA degradation including the cis-acting sequences that determine relative half-life, the trans-acting proteins that recognize such sequence, and the enzymatic mechanisms through which such cis- and trans-acting factors operate. We will then present two examples of individual genes encoding a chemokine and a chemoattractant receptor, which provide insight into the signaling pathways and mechanisms through which mRNA instability and stabilization are controlled in response to extracellular stimulation. Although both mRNAs are constitutively unstable and stabilized in response to stimulation through TLR activation, these responses demonstrate the diversity of mechanisms operating in post-transcriptional regulation.

MECHANISMS REGULATING mRNA DEGRADATION

Adenine-uridine (AU)-rich sequences: structure and function
AU-rich sequence elements (AREs) were identified as determinants of mRNA instability more than two decades ago [17 , 18 ]. Since those early studies, it is clear that AREs are responsible for regulating the decay of many mRNAs [10 , 13 , 19 ]; indeed, 5–8% of the human transcriptome contain ARE motifs within the 3' untranslated regions (UTRs) of the resulting mRNA [20 ]. The core sequence is a nucleotide pentamer containing the AUUUA motif [19 ]. This element is often linked with a surrounding U-rich sequence or is assembled in overlapping AUUUA pentamers, but ARE motifs may also have no core pentamer content [19 , 21 ].

These AREs are now known to interact with sequence-specific, RNA-binding proteins, which serve to coordinate instability or enhanced stability, depending on the circumstance [11 , 22 23 24 25 ]. The most thoroughly studied include tristetraprolin (TTP) [26 ], ARE/poly(U)-binding/degradation factor-1 {AUF-1; also known as heterogeneous nuclear ribonucleoprotein D [27 , 28 ]}, and the ubiquitous member of the mammalian embryonic lethal abnormal visual system family, human antigen R [23 , 29 ]. Although all have been implicated in controlling the instability (or stability) of various mRNAs in response to stimulus, a full understanding of the mechanisms responsible for regulating the post-transcriptional expression of unstable inflammatory mRNAs remains only poorly understood.

Nevertheless, there is a significant body of evidence that demonstrates the importance of mRNA stability as a regulator of the inflammatory response. This is documented most dramatically for the mRNA encoding the master inflammatory regulator TNF-{alpha} [26 , 30 , 31 ], and TNF-{alpha} mRNA contains a clustered AUUUA pentamer motif that confers instability, sensitivity to stimulus-driven stabilization, and stimulus-sensitive control of translational efficiency. Mice expressing a TNF-{alpha} gene, in which the ARE motif has been deleted, exhibit a postnatal systemic inflammatory syndrome, which is characterized by elevated TNF-{alpha} expression, widespread inflammatory cell infiltrates, inflammatory bowel disease, polyarthritis, and death within 4–6 weeks of birth [31 32 33 ]. The TNF-{alpha} 3' UTR ARE is known to be recognized by the potent mRNA-destabilizing protein TTP and mice in which this gene has been deleted through homologous recombination exhibit a phenotype identical to those in which the ARE motif has been deleted [34 ]. More recently, mice in which the AUF-1 gene has been deleted have been characterized, and although the phenotype appears to be milder than that seen with the deletion of TTP, the expression of inflammatory cytokines including IL-1β and TNF-{alpha} was seen to be disregulated [28 ].

Deadenylation, decapping, and exonucleolase activities
Studies in yeast have provided a reasonable view of the generic mechanisms associated with the degradation of mRNAs [8 , 35 , 36 ]. The 3' and 5' ends of mRNAs are protected by the poly A tail and the 7-methyl guanosine cap, respectively, and the removal of one or both represents the early steps in mRNA degradation in the cytoplasm [37 , 38 ]. Following the deprotection reactions, the RNA molecule becomes a ready substrate for 5'–3'- and 3'–5'-directed exonucleases. The predominant mechanism operating in mammalian cells appears to be 3'–5'-directed degradation, which is carried out by a large complex of exonucleases—the exosome [39 ]. Several studies have demonstrated recently that the proteins binding instability determinants such as AREs also have the capacity to interact with the enzymatic machinery necessary for deadenylation, decapping, and exonucleolytic degradation [40 41 42 ]. Hence, at least one mechanism through which AREs promote mRNA decay is through enhancing the assembly of complexes that can carry out the various enzymatic steps requisite for full degradation.

MODELS FOR THE POST-TRANSCRIPTIONAL CONTROL OF CHEMOKINE AND CHEMOATTRACTANT RECEPTOR EXPRESSION

Chemokines
The mRNAs encoding neutrophil-directed chemokines, such as IL-8 in humans and CXCL1 or KC in the mouse, are well-known to be unstable and subject to stimulus-induced mRNA stabilization [15 , 16 , 43 44 45 ]. That instability and the associated stabilization response are critical determinants of the expression pattern for these genes is evident from the finding that they show different inducibility in response to IL-1{alpha}/β as compared with TNF-{alpha} [15 , 16 ]. Although both agents are potent transcriptional activators based on their ability to stimulate the nuclear localization of NF-{kappa}B, only IL-1 provides the additional signal that results in stabilization of chemokine mRNAs. LPS is also known to be a potent inducer of these chemokines and has been reported to promote significant mRNA stabilization as well [45 ]. Hence, activation of the Toll-IL-1 receptor (TIR) family can initiate the signaling pathways that mediate not only the transcription of chemokine genes but also promote stabilization of their cytoplasmic mRNAs. In addition to TIR-mediated signals, IL-17 has been reported to promote enhanced stabilization of TNF-{alpha}-induced, inflammation-related mRNAs including cyclooxygenase 2, IL-6, and IL-8 [46 47 48 ]. Our preliminary findings also demonstrate that IL-17 can promote enhanced stability of KC mRNA and that this operates independently of TNF-{alpha} and the activation of NF-{kappa}B (J. Hartupee, Caini Lin, M. Novotny, X. Li, T. Hamilton, manuscript in preparation). IL-1 and IL-17 appear comparable in their ability to promote mRNA stabilization but different in their respective transcriptional activation potencies, suggesting that there are separable signaling pathways, which couple to transcriptional and post-transcriptional controls.

One of the inherent difficulties in studies of mRNA instability and stimulus-induced stabilization is the fact that for many such mRNAs, the same stimulus that promotes enhanced transcription will also result in stabilization of the mRNA. Hence, when the mRNA is detected, the signals promoting enhanced stability have already been provided, and it is difficult to demonstrate constitutive instability or stimulus-mediated, enhanced stabilization. To determine the behavior of specific mRNAs in the absence of the normal inducing stimulus, we have used the tetracycline-regulated expression system in which the target mRNA is controlled transcriptionally by the interaction of a tet repressor-VP16 fusion protein with a tet-responsive promoter element [45 ]. In this system, the tet-regulated gene is transcribed with high efficiency in the absence of tetracycline or its analog doxycycline (Dox), and transcription is extinguished rapidly following the addition of Dox to the culture medium. This allows the assessment of mRNA half-life without the need for broadly acting and toxic transcriptional inhibitors such as actinomycin D. Using this system, we have observed that KC mRNA is constitutively unstable and highly sensitive to stabilization in response to IL-1 and LPS in several different cell settings [45 , 49 ].

This system also enables the analysis of sequence, which contributes to instability and stimulus sensitivity. For example, deletion of the ARE motifs found in the KC 3' UTR eliminates the instability and of course, the associated stabilization following IL-1 or LPS stimulation [45 , 49 ]. Using this analytic approach, we have been able to identify at least three distinct and functionally independent motifs that regulate the post-transcriptional control of KC gene expression (see Fig. 1 ). The first is a series of four AUUUA [49 ] pentamers arranged in two overlapping sets, which confers modest instability as well as stimulus-mediated control of mRNA translational efficiency [49 ]. This motif is quite similar to that found in the TNF-{alpha} 3' UTR, which is well-described to confer translational control [24 , 50 ]. The second two motifs are contained within the remaining 400 nucleotides of the 3' UTR. The first of the functional elements in this region is represented by the three independent AUUUA pentamers. Mutation of these three pentamers only modestly compromises the constitutive instability and IL-1-induced stabilization of KC mRNA but eliminates sensitivity to the destabilizing protein TTP (T. A. Hamilton, M. Novotny, S. Datta, P. Mandal, J. Hartupee, J. Tebo, X. Li, unpublished). Finally, a primary determinant of instability that is highly sensitive to the action of IL-1 appears to be located at the very 3' end of the molecule and depends on the sequence found in the region containing the third pentamer as well as in the final AU-rich region (AU1). The presence of multiple, functionally independent determinants of post-transcriptional regulation demonstrates that the control of gene expression at this mechanistic level contains a substantial degree of diversity and provides the opportunity for control of mRNA stability via combinatorial action of multiple elements.


Figure 1
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  		Figure 1. KC mRNA 3' UTR contains multiple, functionally independent instability determinants. KC mRNA is 952 nucleotides, which includes a 3' UTR of ~600 nucleotides in length containing seven AUUUA pentamer (P1–3) motifs (indicated in green) with associated AU-rich sequences (indicated in yellow). The pentamers are arranged to include a clustered set of four in two overlapping pairs and three isolated motifs. Three regions confer independent forms of post-transcriptional control. The clustered ARE fragment encodes modest instability and stimulus-sensitive, translational control. The fragment containing the three isolated pentamers confers instability and little stimulus sensitivity for mRNA stabilization (ref. [49 ] and M. Novotny, S. Datta, P. Mandal, J. Hartupee, J. Tebo, X. Li, unpublished). The AU region containing the third pentamer also confers instability and in addition, provides TLR-induced stabilization (T. A. Hamilton, M. Novotny, S. Datta, P. Mandal, J. Hartupee, J. Tebo, X. Li, unpublished).

 
Chemoattractant receptors
There are multiple examples of chemoattractant receptors that exhibit short half-lives, and this appears to be an important feature of the regulation of their expression [51 , 52 ]. These include receptors recognizing endogenous chemokines as well as bacterial products that also serve to stimulate leukocyte chemotaxis [51 52 53 ]. The receptor recognizing formylated bacterial peptides (FPR1) and several related members of the family have been reported to show inducible expression in response to a variety of extracellular stimuli including several TIR ligands [54 55 56 ]. Although the induction of FPR1 mRNA does involve an increase in transcription initiation, FPR1 mRNA can be highly unstable, exhibiting a half-life of approximately 90 min [56 ]. It is interesting that the stimulation of macrophages and neutrophils with LPS can promote a substantial change in the half-life of this mRNA, and we hypothesize that this stabilization is an important feature controlling the stimulus-mediated, enhanced expression. The gene encoding FPR1 contains no introns within the coding or 3' UTR [57 ]. Moreover, the 3' UTR is quite short, containing only ~115 nucleotides and no sequence resembling an ARE. By comparison with the study of ARE-containing chemokine mRNAs such as KC, our understanding of the regulation FPR1 mRNA decay is relatively preliminary. Nevertheless, the distinct sequence features suggest that the sequence element and mechanisms involved in determining FPR1 mRNA instability are distinct from those that operate on chemokine mRNAs such as KC.

Two distinct signal transduction pathways regulate chemokine and chemoattractant receptor mRNA stabilization
Although LPS is able to stimulate the enhanced stability of KC and FPR1 mRNAs, several lines of evidence indicate that these responses are linked with distinct signal transduction events. First, the collection of stimuli, which are able to induce KC or FPR1 mRNA stability, is distinct (see Table 1 ). KC mRNA stablization is seen in multiple cell populations following stimulation with IL-1{alpha}/β and in mononuclear phagocytes following stimulation with LPS [16 , 45 ]. Preliminary findings indicate that other TIR ligands including lipopeptides (TLR2) and CpG oligonucleotides (TLR9) are also able to promote enhanced stability of KC mRNA (T. A. Hamilton et al., unpublished). All TLRs, however, are not competent to produce this response, as evidenced by the inability of TLR3 to promote enhanced stability or significant accumulation of KC mRNA [58 ]. Polyinosinic cytidylic acid (poly IC), a model, double-stranded RNA ligand for TLR3, promotes only weak KC expression, which does not include enhanced mRNA stability. This deficiency is a consequence of the fact that TLR3 uses a distinct TIR adaptor protein, TIR domain-containing adaptor-inducing IFN-β (TRIF), and is the only TLR that does not depend on Myd88 (see Fig. 2 ). The spectrum of agents capable of inducing FPR1 mRNA, including the enhanced stability, clearly distinguishes this response from that involved in controlling the stability of KC mRNA (Table 1 ) [56 ]. For example, the induction of FPR1 mRNA in response to LPS appears to be at least partially dependent on the production of a secreted factor. Although there are likely to be multiple secretory products involved, TNF-{alpha} has the capacity to stimulate FPR1 expression including stabilization of the mRNA. Although TNF-{alpha} can serve as a potent transcriptional stimulus for the KC gene in non-myeloid cells, it is a poor inducer of KC mRNA accumulation as a result of its failure to promote enhanced mRNA stability [15 , 16 ]. In addition, poly IC is able to promote FPR1 stabilization but does not promote KC mRNA stabilization [56 ]. Although circumstantial, these findings demonstrate that the two mRNAs exhibit a different pattern of sensitivity for stabilization in response to a selection of extracellular stimuli.


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  		Table 1. KC Versus FPR1: Differential Control of mRNA Half-Life

 

Figure 2
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  		Figure 2. Multiple TLR4 signaling pathways are coupled to mRNA stabilization via distinct mechanisms. LPS uses TLR4 as the primary signal initiator and recruits the TIR domain-containing adaptor proteins Myd88, TIR domain containing adaptor protein (TIRAP), TRIF, and TRIF-related adaptor molecule (TRAM). Myd88 and TIRAP couple with I{kappa}B kinase (IKK), resulting in the activation of NF-{kappa}B. In addition, these adaptors are linked to activation of the MAPK pathways including ERK, JNK, and p38. The p38 pathway, in particular, has been linked with post-transcriptional controls including mRNA stabilization and translation. TRIF and TRAM are necessary for the activation of IFN regulator factor 3 (IRF3) through the intermediate function of two additional, IKK-related kinases, TANK-binding kinase 1 (TBK1) and IKK{epsilon}. TLR3, the receptor for double-stranded RNA, uses only TRIF as an adaptor and couples primarily to the TBK1/IKK{epsilon}/IRF3 pathway, although this receptor also produces delayed activation of NF-{kappa}B and MAPKs. TLR3 and the TRIF/TRAM adaptors are unable to promote mRNA stabilization as illustrated by the green-highlighted pathways. The activation of NF-{kappa}B also appears to be necessary to promote the transcription of FPR1 mRNA. Acting through a distinct pathway, which is characterized by sensitivity to LY294002 (LY2) and LY303511 (LY3) inhibitors (but not other PI-3K inhibitors), LPS can also promote the enhanced stability of FPR1 mRNA. These pathways are clearly separate based on their relative sensitivity to inhibitors targeting the p38 kinase cascade (green) or the LY-sensitive (purple) pathways that couple independently to KC or FPR1 mRNA stabilization. MD2, Myeloid differentiation protein-2.

 
The second line of evidence involves distinctions between the signaling events downstream of receptor occupancy, which are requisite for the acquisition of enhanced stability of the two mRNAs (see Fig. 2 ). There is a substantial body of evidence supporting the involvement of the p38 stress-activated kinase pathway in promoting the stabilization of AU-rich, short-lived mRNAs in response to stimulation through TLRs [33 , 59 60 61 62 ]. Antagonism of the p38 pathway is associated with diminished stability (and hence, expression) of such mRNAs, and constitutively active kinases at multiple levels of the cascade can activate the response independently. In some circumstances, the AU-rich, RNA-binding protein TTP may be an endpoint substrate for the p38 cascade, linking this signaling pathway to modulation of mRNA stability [63 64 65 66 ]. It is interesting that the LPS-induced stabilization of FPR1 mRNA is not affected by manipulation of p38 signaling intensity [67 ]. In contrast, the LPS-mediated stabilization of FPR1 mRNA is blocked fully by the compound LY2, which is a well-known inhibitor of PI-3K, and the effects of this agent on FPR1 mRNA stability suggested that this pathway might be involved. Although LPS can activate PI-3K, several observations demonstrate that the ability of LY2 to block LPS-induced FPR1 mRNA stabilization is not mediated by PI-3K. Particularly, another inhibitor of PI-3K (i.e., wortmannin) was able to block PI-3K activation fully by LPS but had no effect on FPR1 mRNA expression [67 ]. In addition, a structural homologue of LY2, which is inactive on PI-3K (LY3), retains its activity in blocking FPR1 expression. Hence, it appears that LPS (and perhaps other TLR ligands) use a novel signaling pathway to regulate the expression of the FPR1 gene through stabilization of FPR1 mRNA. This pathway does not, however, regulate the stability of KC, as neither the LY2 nor the LY3 compound has any inhibitory capacity on the LPS-mediated stabilization of KC mRNA [67 ]. Thus, it appears that TLRs can couple to distinct signaling events, which can regulate stability of distinct mRNA targets independently (see Fig. 2 ).

PERSPECTIVES AND CONCLUSIONS

The transient nature and destructive potential of tissue inflammation provide strong justification for the existence of stringent, regulatory control of the process. The contribution of transcriptional control mechanisms in such transient responses is now well-recognized, and many of the important molecular participants in the regulation of inducible transcription have been identified and studied in detail. It is now evident, however, that additional controls operate post-transcriptionally, and although temporally, these are second in line, they exert equally important oversight of the process.

Although the existence of differential mRNA decay driven by AU-rich sequences in mRNAs was identified over 20 years ago, the spectrum of mRNAs that exhibit control at this level and the molecular basis for this diversity are only now being recognized. The mechanistic heterogeneity is evident in several aspects of the process. Certainly, there is emerging recognition of the complexity of AU-rich sequences and their linkage with distinct patterns of post-transcriptional control, which includes not only the rate of mRNA decay but also its translational efficiency. Further complexity and hence, diversity arise when considering the sequence-specific binding proteins that are the means through which altered mRNA metabolism is achieved. Finally, it is clear that there is also substantial diversity in the nature of the signaling pathways through which these mechanisms are controlled by extracellular stimuli.

Several examples from genetically modified mice demonstrate the potential role of mRNA stability in the pathogenesis of autoimmunity and chronic inflammatory disorders. As described earlier, the manipulation of the ARE motif in the TNF-{alpha} gene and the gene products that control the function of this sequence provide remarkable insight into the magnitude of the impact of post-transcriptional control in regulating biological responses. Although it appears highly likely that genetic variation in the various determinants of the post-transcription control of inflammation will be an important mechanism in human disease, this remains the target for much future research.

Received December 22, 2006; revised February 7, 2007; accepted February 20, 2007.

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