5, 8, 11, 14-eicosatetraynoic acid suppresses CCL2/MCP-1 expression in IFN-γ-stimulated astrocytes by increasing MAPK phosphatase-1 mRNA stability
© BioMed Central Ltd 2012
Received: 26 September 2011
Accepted: 18 February 2012
Published: 18 February 2012
The peroxisome proliferator-activated receptor (PPAR)-α activator, 5,8,11,14-eicosatetraynoic acid (ETYA), is an arachidonic acid analog. It is reported to inhibit up-regulation of pro-inflammatory genes; however, its underlying mechanism of action is largely unknown. In the present study, we focused on the inhibitory action of ETYA on the expression of the chemokine, CCL2/MCP-1, which plays a key role in the initiation and progression of inflammation.
To determine the effect of ETYA, primary cultured rat astrocytes and microglia were stimulated with IFN-γ in the presence of ETYA and then, expression of CCL2/MCP-1 and MAPK phosphatase (MKP-1) were determined using RT-PCR and ELISA. MKP-1 mRNA stability was evaluated by treating actinomycin D. The effect of MKP-1 and human antigen R (HuR) was analyzed by using specific siRNA transfection system. The localization of HuR was analyzed by immunocytochemistry and subcellular fractionation experiment.
We found that ETYA suppressed CCL2/MCP-1 transcription and secretion of CCL2/MCP-1 protein through up-regulation of MKP-1mRNA levels, resulting in suppression of c-Jun N-terminal kinase (JNK) phosphorylation and activator protein 1 (AP1) activity in IFN-γ-stimulated brain glial cells. Moreover, these effects of ETYA were independent of PPAR-α. Experiments using actinomycin D revealed that the ETYA-induced increase in MKP-1 mRNA levels reflected an increase in transcript stability. Knockdown experiments using small interfering RNA demonstrated that this increase in MKP-1 mRNA stability depended on HuR, an RNA-binding protein known to promote enhanced mRNA stability. Furthermore, ETYA-induced, HuR-mediated mRNA stabilization resulted from HuR-MKP-1 nucleocytoplasmic translocation, which served to protect MKP-1 mRNA from the mRNA degradation machinery.
ETYA induces MKP-1 through HuR at the post-transcriptional level in a receptor-independent manner. The mechanism revealed here suggests eicosanoids as potential therapeutic modulators of inflammation that act through a novel target.
Inflammatory responses in the brain contribute to the pathogenesis of neurodegenerative disease, such as Alzheimer's disease, multiple sclerosis, and brain ischemia [1–4]. These responses are characterized by a sequential process involving the release of pro-inflammatory cytokines, increased expression of endothelial adhesion molecules and chemotactic factors, and activation of brain immune effector cells [5, 6].
Microglia and astrocytes are representative immune cells in the brain. When microglia and astrocytes become activated by a variety of stimuli, they produce inflammatory cytokines and chemokines, which accelerate disease progression [7–11]. Among the inflammatory chemokines elaborated, glial cell-derived CCL2/MCP-1 is crucial: by promoting the migration and recruitment of inflammatory cells, it is primarily responsible for the initiation and progression of inflammatory responses . In an animal model of prion disease, mice deficient in CCL2/MCP-1 showed a delayed onset of inflammatory disease and an increase in survival time . CCL2/MCP-1 overexpression is also associated with a variety of disease states, including atherosclerosis [14, 15] and ischemic stroke . Therefore, intervention aimed at suppressing CCL2/MCP-1 expression is an emerging therapeutic strategy for the treatment of neurodegenerative diseases.
As a part of this therapeutic approach, peroxisome proliferator-activated receptors (PPARs) have received recent research attention. PPARs, which comprise three members--α, γ and β/δ--are ligand-activated transcription factors that form a subfamily of the nuclear receptor gene family. PPARs were originally reported to be highly expressed in adipocytes and were shown to play important roles in adipocyte differentiation, lipid biosynthesis, and glucose homeostasis [17, 18]. However, subsequent studies have suggested that each PPAR subtype has anti-inflammatory effects in various cell types [19, 20]. One of them, PPAR-α, exerts its anti-inflammatory functions by negatively regulating the expression of pro-inflammatory molecules [21–23]. In the brain, PPAR-α activators have been shown to inhibit the production of nitric oxide and the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 in glial cells [24–26]. Thus, PPAR-α activators have shown promising beneficial effects in several animal models of CNS disorders in which an inflammatory component is strongly implicated, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, and ischemic brain injury [27–29].
Although significant advances have been made in our understanding of the molecular mechanisms of PPAR-α activators during metabolic processes, much less is known about the anti-inflammatory mechanisms of PPAR-α activators during inflammation. For example, accumulating evidence suggests that PPAR activators act in a receptor-independent manner in various cell types. In one such case, the PPAR-γ activator, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), was shown to suppress inflammatory cytokines in a receptor-independent manner [30–32]. Activators of PPAR-α have also proven effective against experimental autoimmune encephalomyelitis (EAE) independent of PPAR-α . Thus, PPAR activators are multifaceted modulators of inflammatory responses, functioning through both receptor-dependent and -independent mechanisms.
Here, we evaluated the anti-inflammatory effects of three fibrates, WY14643, fenofibrate, clofibrate, and the eicosanoid, 5,8,11,14-eicosatetraynoic acid (ETYA), as PPAR-α activators. Our results showed that ETYA, but not fibrates, acted through a PPAR-α-independent mechanism to suppress JNK-mediated CCL2/MCP-1 expression by inducing MKP-1 (MAPK phosphatase), a negative regulator of MAPK. ETYA-induced MKP-1 expression resulted from a HuR-mediated increase in MKP-1 mRNA stability. These findings suggest an additional therapeutic use of known anti-inflammatory agents based on a novel mechanism targeting post-transcriptional regulation.
Materials and methods
IFN-γ was purchased from Calbiochem (Butler Pike, PA). Antibodies against phospho-JNK, phospho-MKP-1 and histone deacetylase (HDAC)1 were purchased from Cell Signaling (Beverly, MA). Anti-MKP-1, anti-HuR, anti-decaping protein (DCP)1α, anti-T cell internal antigen (TIA)1, anti-TIA1 related (TIAR), Lamin B, GAPDH and methyl CpG binding domain (MBD)3 antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). ETYA, WY-14643, clofibrate, and 2-arachidonylglycerol (2-AG) were purchased from BIOMOL (Plymouth Meeting, PA). Fenofibrate and actinomycin D (Act D) were purchased from Sigma (St. Louis, MO).
Primary microglia and astrocytes were cultured from the cerebral cortices of 1-day-old Sprague-Dawley rats. Cortices were triturated into single cells in minimal essential media (MEM) containing 10% fetal bovine serum (Hyclone, Logan, UT), plated onto 75-cm2T-flasks, and cultured for 2 weeks. Following the removal of microglia, primary astrocytes were isolated by trypsinization. Microglia and meningeal cells were depleted by incubating astrocytes in serum-free MEM for 2 days before use. Final cultures were shown to consist of more than 95% authentic astrocytes by glial fibrillary acidic protein (GFAP) staining.
Reverse transcription-polymerase chain reaction (RT-PCR) and quantitative RT-PCR analysis
Total RNA was isolated using TRIzol (Invitrogen, Carlsbad, CA), and cDNA was prepared using Avian Myeloblastosis Virus reverse transcriptase (GenDEPOT, Barker, TX), according to the manufacturers' instructions. Conventional PCR was performed using 32 cycles of sequential reactions. The following primer pairs for the indicated targets were purchased from Bioneer (Daejeon, Korea): GAPDH, 5'-TCC CTC AAG ATT GTC AGC AA-3' (forward) and 5'-AGA TCC ACA ACG GAT ACA TT-3' (reverse); TNF-α, 5'-GTA GCC CAC GTC GTA GCA AA-3' (forward) and 5'-CCC TTC TCC AGC TGG GAG AC-3' (reverse); CCL2/MCP-1, 5'-ATG CAG GTC TCT GTC ACG CT-3' (forward) and 5'-CTA GTT CTC TGT CAT ACT GG-3' (reverse); MKP-1, 5'-AGG ACA CCA CAA GGC AGA C-3' (forward) and 5'-TGA TGG GGC TTT GAA GGT AG-3' (reverse); PPAR-α, 5'-TTC GGA AAC TGC AGA CCT-3' (forward) and 5'-TTA GGA ACT CTC GGG TGA T-3' (reverse); cannabinoid receptor (CB)1, 5'-TCC CAG GGA GAG GAG AGT GT-3' (forward) and 5'-GCC GTC ACC AGG TTT TCA CT-3' (reverse). For quantitative PCR, the amplification reactions were performed with KAPA SYBR qPCR master mix (KAPA Biosystems, Woburn, MA) according to the manufacturer's specifications. Amplification conditions were as follows: 40 cycles of 3 s at 95°C, 15 s at 55°C, and 15 s at 72 C. After amplification was complete, a melting curve was generated by heating at 1°C per second to 95°C. Melting curves were generated and data were quantitatively analyzed using Rotor Gene Q, version 1.7. The sequences of primers for quantitative RT-PCR were as follows: CCL2/MCP-1, 5'-ATG CAG TTA ATG CCC CAC TC-3' (forward) and 5'-TTC CTT ATT GGG GTC AGC AC-3' (reverse); MKP-1, 5'-TAG ACT CCA TCA AGG ATG CTG G-3' (forward) and 5'-GCA GCT CGG AGA GGT TGT GAT-3' (reverse); GAPDH, 5'-GGC CAA AAG GGT CAT CAT C-3' (forward) and 5'-GTG ATG CCA TGG ACT GTG G-3' (reverse).
Western blot analysis
Cell lysates for Western blot analysis, prepared as previously described , were separated by SDS-PAGE and transferred to nitrocellulose membranes. Membranes were incubated with primary antibodies and HRP-conjugated secondary antibodies, and bands were visualized using an enhanced chemiluminescence system (Ab Frontier, Korea).
EMSAs were conducted following a previously reported method . The oligonucleotide probe, 5'-CCT GAC TCC ACC TCT GGC-3', specific for the AP1 binding site of the rat CCL2/MCP-1 promoter (positions -129 to -111) was purchased from Bioneer. For supershift experiments, protein extracts were incubated with 0.2 μg of anti-c-Jun antibody (Santa Cruz Biotechnology) for 1 h prior to the addition of γ-32P-labeled probe.
Primary microglia and astrocytes were seeded onto 6-well plates. After incubating cells with IFN-γ in the presence or absence of ETYA or fibrates, 500 μl of cell-conditioned media was collected and assayed using rat CCL2/MCP-1 ELISA kits (BD Biosciences, San Diego, CA), according to the manufacturer's instructions.
Construction of luciferase reporter plasmids and luciferase assay
Rat CCL2/MCP-1 promoter fragments corresponding to positions -3554 to +76 (pGL3-CCL2/MCP-1), -2355 to -81 (pGL3-κB-AP1-SP1), -2404 to -2062 (pGL3-κB) and -228 to +45 (pGL3-AP1-Sp-1) were amplified by PCR using rat genomic DNA as a template and specific primer sets. Transient transfections were performed using Lipofectamine 2000 reagents (Invitrogen) as described by the manufacturer. After incubating transfected cells for 48 h, luciferase activity was measured using a luminometer (PerkinElmer Vitor3) and normalized to β-galactosidase activity (measured at A 420)
ChIP assays were performed as described previously . Cell supernatants were immunoprecipitated with anti-c-Jun antibodies overnight at 4°C; protein-bound, immunoprecipitated DNA was recovered by phenol/chloroform extraction and then amplified by PCR using the primer pair, 5'-TTC CAC TCT CCA TCG CTC AT- 3' (forward) and 5'-TCT GCA TTT CTA GCG GCT CT-3' (reverse), spanning the promoter region of CCL2/MCP-1 (position -155 to -71) containing AP1 elements.
Immunostaining and confocal microscopy
Astrocytes cultured on poly-D-lysine-coated coverslips were fixed with methanol at -20°C for 30 min. Fixed cells were incubated with anti-HuR and anti-GFAP (Sigma) antibodies at 4°C overnight, and then with fluorescein- or rhodamine-conjugated secondary antibodies (Molecular Probes, Eugene, OR) for 2 h. Coverslips were slide-mounted and observed under a confocal microscope (Zeiss, Germany).
Synthesis and transfection of small interfering RNA
siRNA duplex oligonucleotides targeting MKP-1 (5'-CCA ATT GTC CTA ACC ACT T-3'), CB1 (5'-CGA AGG UGA CCA UGU CUG UTT-3'), HuR (5'-GAU GCC AAC UUG UAC AUC ATT-3') and PPAR-α (5'-GGC UAA AGC UGG CGU ACG AUU-3') were chemically synthesized by Bioneer (Korea). Confluent astrocytes and microglia were transfected with siRNA oligonucleotides using Lipofectamine RNAiMAX (Invitrogen), according to the manufacturer's instructions. All assays were performed at least 48 h after siRNA transfection.
Cell extracts were prepared by immunoprecipitation, as previously described . Briefly, lysates (300 μg) were incubated with an anti-MKP-1 antibody (1 μg) at 4°C overnight, and precipitated by incubating with protein G-agarose beads (Upstate Biotechnology) for 2 h at 4°C. Phosphatase activity was measured in two ways. In the first, MKP-1 activity was measured by incubating immunoprecipitated proteins with the substrate, p-nitrophenylphosphate (p-NPP) (Sigma), for 4 h at 37°C followed by spectrophotometric analysis at 405 nm. In the second, specific p-JNK-linked MKP-1 activity was measured by incubating immunoprecipitated proteins with lysates from IFN-γ-stimulated astrocytes (as substrates). Bead-protein conjugates and lysates were then boiled, and the resulting eluates were analyzed by Western blotting using antibodies against MKP-1 or phospho-JNK.
Differences among groups were determined using one-way ANOVA. A p-value of 0.05 was considered statistically significant. Values are presented as means ± SEMs or ± SDs
ETYA suppresses CCL2/MCP-1 transcription and protein secretion by inhibiting AP1 signaling in IFN-γ-activated brain astrocytes
The suppressive actions of ETYA on JNK/AP1 are mediated by MKP-1 and are independent of PPAR-α
Because ETYA is known as a PPAR-α activator , we examined whether the actions of ETYA on MKP-1 are receptor-dependent or independent. As shown in Figure 3G and 3H, ETYA-induced MKP-1 expression was not reversed by siRNA-mediated PPAR-α knockdown; CCL2/MCP-1 expression levels were also unaffected (Figure 3I) suggesting that ETYA acted in a receptor-independent manner.
CCL2/MCP-1 suppression by ETYA in brain microglia is also mediated by the induction of MKP-1
ETYA increases MKP-1 mRNA stability by inducing HuR cytoplasmic translocation
MKP-1 mRNA stabilization is mediated by various RNA binding proteins (RNA-BPs), including NF-90 and HuR . Previous study showed that HuR influences MKP-1 stability through binding to MKP-1 AU-rich elements (AREs) in the 3'-untranslated region (UTR) [41–43]. We thus inferred that HuR was involved in ETYA-induced MKP-1 mRNA stabilization mechanism. To determine this possibility, we tested the effects of siRNA against HuR on MKP-1 mRNA levels. As shown in Figure 5B and 5C, siRNA-mediated HuR knockdown inhibited the stabilizing effect of ETYA on MKP-1 mRNA. Because the influence of HuR on the expression of target mRNAs is linked to its cytoplasmic export, we next examined whether ETYA induced HuR cytoplasmic translocation. The results of subcellular fractionation experiments showed that ETYA increased the cytoplasmic translocation of HuR, but had no effect on other RNA-BPs (Figure 5D); this effect was also confirmed using an immunocytochemical approach. Namely, HuR was shown to retain its nuclear localization in untreated astrocytes, whereas in cells treated with ETYA, HuR was partly displaced into the cytoplasm (0.5 h), and over time, appeared in a spotted fashion in the cytoplasm (2 h) (Figure 5E). Taken together, these results suggest that ETYA induces MKP-1 mRNA stability by increasing HuR cytoplasmic translocation.
MKP-1, a dual specificity (Ser/Thr or Thr/Tyr) protein phosphatase, is responsible for the inactivation of JNK/p38, and therefore controls MAPK-dependent inflammation during the innate immune response . The roles of MKP-1 in inflammation are relatively well identified, and our previous studies also showed that 15d-PGJ2, a PPAR-γ activator, suppressed brain glial cell-mediated inflammatory responses through regulation of MKP-1 . However, the detailed mechanism by which MKP-1 expression was regulated by PPAR activators remained to be established. MKP-1 expression could be regulated at transcriptional or post-transcriptional levels. Although several transcription factors, including SP1, SP3 and AP1, are known to be involved in the transcriptional regulation of MKP-1 in response to growth factors and stress stimuli [37, 38], it is unlikely that ETYA acts through such a mechanism because it had no effect on the activity of these transcription factors (data not shown). Instead, because MKP-1 is an early response gene with a short-lived mRNA, it is likely to be regulated post-transcriptionally. Our study showed that ETYA treatment maintained MKP-1 mRNA levels for up to 5 h after mRNA synthesis was blocked with Act D, revealing that ETYA acted at the post-transcriptional level to increase MKP-1 mRNA stability (Figure 5).
The transient, stimulus-driven stabilization of early response transcripts is controlled by sequence-specific RNA-BPs that influence mRNA metabolism . RNA-BPs that inhibit mRNA decay include the embryonic lethal abnormal vision (Hu/elav) family of RNA-BPs, consisting of the ubiquitous HuR (HuA) protein and the primarily neuronal proteins, HuB (Hel-N1), HuC, and HuD . The most extensively studied member, HuR, binds to the AREs present in 3'-UTR of target mRNA and subsequently translocated to the cytoplasm, where it increases the half-life of many mRNAs, such as cyclooxygenase-2 (COX-2), inducible nitric oxide (iNOS), and MKP-1 [41, 47, 48]. We confirmed that the ETYA-induced increase in MKP-1 stability is mediated by HuR and occurs through the cytoplasmic translocation of HuR. Interestingly, we observed that this cytoplasmic HuR tended to form spot-like aggregates over time (Figure 5). Using a confocal imaging system, we confirmed that these aggregates were co-localized with stress granules (SGs), but not processing bodies (PBs) (Additional file 4: Figure S4). SGs are transient, dynamic cytoplasmic sites containing aggregates of mRNA. Unlike PBs, which contain mRNA decay machinery, SGs consist of translation initiation factors, small ribosomal subunits, and a diverse group of mRNAs and proteins, and are linked to RNA metabolism. Some RNA-BPs, such as tristetraprolin (TTP) and butyrate response factor (BRF)1, a subunit of the RNA polymerase III transcription initiation factor IIIB, destabilize specific transcripts, whereas other stabilizing proteins, such as HuR, bind transcripts for export or storage until stress conditions are alleviated . Thus, SGs are thought to be passive repositories of the untranslated mRNAs that accumulate during stress, and serve to enable reinitiation of translation when environmental conditions improve. In this study, we speculated that ETYA induced a process in which cytosol-exported HuR caused accumulation of MKP-1 mRNA transcripts in SGs, preventing them from decaying under unfavorable conditions.
These observations give rise to a question: how does ETYA induce HuR export to the cytoplasm? Recent reports have shown that phosphorylation of HuR within the hinge region is mediated by protein kinase C (PKC; isoforms α and δ) and cyclin-dependent kinase (Cdk) and these are linked to the nucleocytoplasmic translocation of HuR [50–52]. Phosphorylation of HuR at S158 and S221 by PKC has been implicated in the translocation of HuR to the cytoplasm, whereas Cdk1-mediated phosphorylation at HuR at S202 helps to maintain HuR in the nucleus. Thus, the effects of ETYA on MKP-1 could be achieved by HuR phosphorylation via PKC or Cdk1. To verify this possibility, we first examined whether ETYA induces HuR serine phosphorylation. Immunoprecipitation experiments using nuclear/cytoplasmic extracts revealed that ETYA induced HuR serine phosphorylation (Additional file 5: Figure S5). Although it is reasonable to suppose that these modifications are linked to cytoplasmic translocation, we did not determine which serine residues of HuR are phosphorylated by ETYA. Thus, further studies are needed to clarify which serine sites are phosphorylated by ETYA and which upstream molecules (PKC or Cdk) are regulated by ETYA.
Recently, accumulating evidence suggests that cannabinoids act (directly or indirectly) to suppress inflammation-dependent neurodegeneration via inhibition of pro-inflammatory cytokine expression, and that of reactive oxygen intermediates; several cellular pathways are involved [53, 54]. Of particular interest in this context are recent reports addressing functional interactions between cannabinoids and anti-inflammatory nuclear receptors, including PPARs [55–57]. These studies suggest that a novel mechanism potentiating anti-inflammatory capacity upon brain inflammation may be in play. As endocannabinoids such as anandamide (AEA) and 2-AG are derived from arachidonic acid synthesized within the body, it is likely that endocannabinoids and ETYA share structural and functional similarities . Moreover, recent studies have shown that endocannabinoids not only inhibit the JNK activation induced by inflammatory stimuli [59, 60], but also induce expression of MKP-1 [61, 62]. We found that both 2-AG and ETYA suppressed IFN-γ-induced JNK phosphorylation and CCL2/MCP-1 expression, and inhibited MKP-1 synthesis in rat astrocytes. Further, we determined that the mechanism of 2-AG action was CB1 receptor-dependent but PPAR-α-independent, and that ETYA action did not require either receptor. This means that the signaling mechanisms regulating the level of MKP-1 expression differ in nature (Additional file 6: Figure S6). This results suggest another important point that the eicosanoid, ETYA, and the cannabinoid derivative, 2-AG, which evidence suggests share some structural and functional similarities , regulate MKP-1 in brain glial cells through different mechanisms. Thus, although both agents increased MKP-1 expression, the underlying mechanisms were quite different, with ETYA increasing MKP-1 mRNA levels post-transcriptionally, and 2-AG likely regulating MKP-1 expression at the transcriptional level (Figure S6G, and data not shown). Although the molecular targets of these agents upstream of MKP-1 are not yet known, it is important to note that these structurally similar compounds actively regulate MKP-1 levels through transcriptional and post-transcriptional mechanisms in a target- and cell-specific manner. In this context, identifying the specific underlying mechanism could provide a novel therapeutic target for anti-inflammatory drugs. Importantly, the development of such drugs that target different mechanisms could not only reduce side effects on other organs, but could also eliminate undesirable induction of receptor-dependent target genes.
In this study, we demonstrated a novel anti-inflammatory mechanism of ETYA, a PPAR-α ligand, by increasing HuR-mediated-MKP-1 mRNA stability that leads to the specific suppression of CCL2/MCP-1 during inflammatory processes. ETYA induced HuR-MKP-1 nucleocytoplasmic translocation, which subsequently, served to protect MKP-1 mRNA from the mRNA degradation machinery. These findings establish a novel mechanism in which ETYA increases MKP-1 expression through HuR at the post-transcriptional level in a receptor-independent manner.
This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (R13-2003-019-01006 to I. Jou and NRF-2009-0069505 to J.H. Lee).
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