TY - JOUR
AU - Tsujimoto,, Masafumi
AB - Abstract Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multi-functional enzyme. In this study, we analysed its role in lipopolysaccharide-induced inflammatory response in wild-type and ERAP1-knockout mice. Following lipopolysaccharide injection, ERAP1 was secreted into the blood, increasing leucine aminopeptidase activity and NO synthesis therein. Among the amino acids tested, arginine concentration was significantly increased in wild-type mice compared to ERAP1-knockout mice. These results suggest that ERAP1 behaves similar to acute-phase proteins, which are secreted into the blood in response to infectious/inflammatory stimuli and are involved in enhancing NO synthesis as a host defense mechanism. acute phase, amino acid, aminopeptidase, lipopolysaccharide, nitric oxide Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme belonging to the M1 family of aminopeptidases (1–16). Several studies have indicated that it plays important roles in blood pressure regulation, angiogenesis, ectodomain shedding of cytokine receptors and antigen processing and presentation to MHC class I molecules (5, 17–22). ERAP1 is recognized as a protein retained in the endoplasmic reticulum (21–23). In contrast, we recently found that ERAP1 is secreted from macrophages in response to infectious and/or inflammatory stimuli, such as lipopolysaccharide (LPS)/interferon (IFN)−γ treatment (13, 24). ERAP1 secretion enhances the phagocytic and nitric oxide (NO) synthetic activities of macrophages (13, 14, 16, 24). These findings indicate that secreted ERAP1 plays important roles in the inflammatory response. Epidemiologic and genome-wide association studies unveiled the potential association between single-nucleotide polymorphisms (SNPs) in the ERAP1 gene and susceptibility to several diseases, including hypertension, infectious diseases and autoimmune diseases such as ankylosing spondylitis, psoriasis and Behçet’s disease (5–8, 15, 25–27). Mutagenic studies on ERAP1 gene showed that disease-associated SNPs influence ERAP1 activity (28, 29). These findings strongly suggest that ERAP1 SNP variants play a role in the pathogenesis of several diseases by changing their mRNA expression levels and/or enzymatic activities. To elucidate the relationship between ERAP1 and pathogenesis of several diseases, it is necessary to analyse the function of ERAP1 in vivo. In this study, we examined for the first time whether ERAP1 was secreted into the blood in response to LPS injection in mice to play roles in the host defense processes. Materials and Methods Animals ERAP1-knockout (ERAP1−/−, C57BL/6 background) mice (30) and wild-type mice (ERAP1+/+, C57BL/6) were obtained from the Jackson Laboratory (Bar Harbor, ME, USA). Animal husbandry and all experimental procedures were conducted in accordance with the guidelines for the Science Council of Japan and were approved by the Institutional Animal Care and Use Committee of Teikyo-Heisei University. Animals were maintained under controlled air conditions (room temperature, 24 ± 1°C; humidity, 50 ± 5%) with food and water available ad libitum and were housed under a light/dark (LD) cycle of 12 h of light (light intensity, 200–300 lux) and 12 h of darkness, until sampling. Preparation of serum Male mice aged 4–6 months were injected intraperitoneally with Escherichia coli O55: B5 LPS (Sigma-Aldrich, St. Louis, MO, USA) at dose of 1 mg/kg body weight or with phosphate buffered saline (PBS). At desired intervals after LPS injection, mice were euthanized, and blood samples were collected by decapitation. For serum preparation, blood samples were incubated at room temperature for 30 min and further incubated at 4°C for 16 h to allow blood coagulation. The coagulated blood was then centrifuged at 2,300 × g for 15 min at 4°C. The supernatant obtained was the serum used for further analysis. Western blot analysis Five microlitres of serum was analysed by western blotting to detect ERAP1, as previously described in (13). Protein blots were probed using anti-ERAP1 antibody, followed by an HRP-labelled secondary antibody. The protein bands were detected using a LAS-4000 Mini Luminescent Image Analyzer (GE Healthcare, Chicago, IL, USA) and ECL Prime Western Blotting Detection Kit (GE Healthcare). Densitometric analysis of antibody response was performed by Scion Image software (Scion Corp., Frederick, MD, USA). Measurement of nitric oxide (NO) synthesis For the detection of NO, serum was filtered through an Amicon Ultra-4 Centrifugal Filter Unit (10 kDa cut-off) (Merck Millipore, Darmstadt, Germany). NO synthesis was assessed in the samples by measuring its metabolites, nitrite and nitrate. Nitrite and nitrate amounts were quantified calorimetrically using NO2/NO3 Assay Kit-C II (Dojindo, Kumamoto, Japan). Briefly, 80 μl of filtered serum was treated with 10 μl of Enzyme Cofactors Solution and NO3 Reductase Solution for 2 h. The reactants were incubated with reagent A for 5 min and further incubated with reagent B for 10 min. All reactions were carried out at room temperature. The absorbance of reactants was measured at 550 nm and compared against the absorbance curve of NaNO3 standard solutions. Measurement of leucine aminopeptidase activity Leucine aminopeptidase (LAP) activity was determined using leucine-4-methylcoumaryl-7-amides (Leu-MCA) by adapting a previously described method (13). Briefly, 25 μl serum was mixed with 25 μl PBS containing 200 μM Leu-MCA and incubated at 37°C for 15 min. The concentration of 7-amino-4-methylcoumarin was measured using a multi-microplate reader SH-9000 Lab (Hitachi High Tech, Tokyo, Japan) at excitation and emission wavelengths of 380 nm and 460 nm, respectively. Measured fluorescence intensities were converted to enzymatic activities by using 7-amino-4-methylcoumarin standard curve. Quantitative real-time reverse transcriptase PCR Livers were obtained from the male animals aged 4–6 months after euthanasia. Total liver RNA was isolated by using RNeasy RNA Purification Columns (Qiagen, Venlo, The Netherlands). Extracted RNA was reverse-transcribed using ReverTra Ace (TOYOBO, Shiga, Japan) according to the manufacturer’s instructions. PCR mixtures contained 10 μl TaqMan Fast Advanced Master Mix (Thermo Fisher Scientific, Waltham, MA, USA), 0.5 μl Taqman probe (Thermo Fisher Scientific) for ERAP1 and GAPDH (10 μM) labelled by FAM (6-carboxyfluorescein) and VIC (4,7,2′-trichloro-7′-phenyl-6-carboxyfluorescein) dyes, respectively, 1 μl cDNA, and 8.5 μl ddH2O to reach a total reaction volume of 20 μl. Real-time PCR was performed using delta-delta-Ct method on an ABI StepOnePlus Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) with the following cycling conditions: 1 cycle at 95°C for 20 s, 40 cycles at 95°C for 1 s and 1 cycle at 60°C for 20 s. Fluorescence was measured at the end of each extension step. Threshold cycles (Ct) values were automatically generated by the ABI StepOnePlus software. Each experiment was performed in triplicate and included a non-template control in which 1 μl ddH2O was used instead of the cDNA template. Quantification of free amino acids in serum Levels of free amino acids, l-leucine, l-proline and l-arginine, in the serum were measured by Nihon Doubutsu Tokushu Shindan Co., Ltd, as described previously by Fonteh et al. (31). Statistical analysis All data are representative of at least three-independent experiments and presented as mean ± SD. Statistical analysis was conducted using the Student’s t-test and one-way ANOVA, and P < 0.05 was considered statistically significant (16). The mean values of each group were compared separately using the Tukey–Kramer multiple comparison test. Results and Discussion Secretion of ERAP1 into the blood in response to LPS injection In our previous studies, we showed that ERAP1 is secreted from LPS-activated murine macrophage cell line RAW264.7 and enhances their NO synthetic activity (14, 16). To elucidate the in vivo function of ERAP1, mice were injected intraperitoneally with LPS. As known previously (32), injection of LPS caused a temporal decrease in the total protein level of the serum at 6 h (Fig. 1A). ERAP1 levels in the serum were simultaneously detected at these time points by western blot analysis. Serum levels of ERAP1 increased between 12 and 48 h after injection (Fig. 1B). Quantitative analyses indicated that after a 6 h lag, ERAP1 levels steadily increased until 24 h and then declined (Fig. 1C). Serum ERAP1 levels, 24 h after injection, showed a 5-fold increase compared with the levels at 0 h. Notably, even 48 h post-injection, ERAP1 levels in the serum, remained significantly higher than the 0 h timepoint/corresponding PBS treated control. These results indicate that ERAP1 is secreted into the blood in response to LPS injection. Based on the results, we hypothesize that ERAP1 can be classified as an acute-phase protein, such as C-reactive protein and serum amyloid A, whose serum levels are increased or decreased in response to the early phase of infectious/inflammatory stimuli (33–35). Fig. 1 View largeDownload slide LPS-induced secretion of ERAP1 into the blood. Mice were intraperitoneally injected with LPS, and their serum was collected at different times post-injection. (A) BCA and (B) western blot analysis of collected serum. (C) Densitometric analysis of western blots was performed to compare the ERAP1 levels. ERAP1 levels at each time point were normalized to the 24 h time point. The data are expressed as the mean ± SD. (error bars) of three-independent gels. **P < 0.01; ***P < 0.001. Fig. 1 View largeDownload slide LPS-induced secretion of ERAP1 into the blood. Mice were intraperitoneally injected with LPS, and their serum was collected at different times post-injection. (A) BCA and (B) western blot analysis of collected serum. (C) Densitometric analysis of western blots was performed to compare the ERAP1 levels. ERAP1 levels at each time point were normalized to the 24 h time point. The data are expressed as the mean ± SD. (error bars) of three-independent gels. **P < 0.01; ***P < 0.001. Effects of secreted ERAP1 on aminopeptidase and NO synthetic activities in LPS-injected mice sera We then examined the aminopeptidase activity of secreted ERAP1 during inflammation in mice. Since serum presumably contains several aminopeptidases (36–39), to determine the contribution of ERAP1, we sought to compare the aminopeptidase activities in the sera of wild-type and ERAP1-knockout mice. We first determined the serum levels of ERAP1 in wild-type and ERAP1-knockout mice (Fig. 2A). As expected, an increase in the serum levels of ERAP1 was detected in the wild-type mice upon LPS injection. In contrast, the serum of ERAP1-knockout mice showed no detectable level of ERAP1, either before or after LPS injection. Although a protein band resembling that of ERAP1 was observed in these mice, this band showed a slightly lower molecular weight than that of ERAP1, indicating a different (or cross-reactive) protein from ERAP1. Fig. 2 View largeDownload slide Functional analyses of secreted ERAP1. Sera were collected from wild-type and ERAP1-knockout mice at indicated times after LPS injection. (A) Serum ERAP1 was detected in the wild-type mice but not in the ERAP1-knockout mice. An asterisk indicates possible cross-reactive protein. (B) Leucine aminopeptidase (LAP) activity of secreted ERAP1. Sera were collected from wild-type (open bars) and ERAP1-knockout (closed bars) mice at the indicated times after LPS injection, and LAP activity was measured. (C) Effect of secreted ERAP1 on nitric oxide (NO) synthesis in the serum. Sera were collected from wild-type and ERAP1-knockout mice at the indicated times, and serum NO concentrations were measured. Fig. 2 View largeDownload slide Functional analyses of secreted ERAP1. Sera were collected from wild-type and ERAP1-knockout mice at indicated times after LPS injection. (A) Serum ERAP1 was detected in the wild-type mice but not in the ERAP1-knockout mice. An asterisk indicates possible cross-reactive protein. (B) Leucine aminopeptidase (LAP) activity of secreted ERAP1. Sera were collected from wild-type (open bars) and ERAP1-knockout (closed bars) mice at the indicated times after LPS injection, and LAP activity was measured. (C) Effect of secreted ERAP1 on nitric oxide (NO) synthesis in the serum. Sera were collected from wild-type and ERAP1-knockout mice at the indicated times, and serum NO concentrations were measured. We next examined leucine aminopeptidase (LAP) activities in wild-type and ERAP1-knockout mice sera at different time points post LPS injection (Fig. 2B). Uninjected wild-type and ERAP1-knockout mice showed comparable LAP activity, suggesting that ERAP1 has little effect on the basal LAP activity in the serum. Twelve hours after the injection, when ERAP1 concentration peaked in the serum of wild-type mice, 20% higher LAP activity was observed in wild-type mice, compared to ERAP1-knockout mice. This established the contribution of ERAP1 as a serum aminopeptidase, upon LPS injection. At 24 h, LAP activity attributable to ERAP1 in wild-type mice reduced to ∼10%. It is presumable that aminopeptidases other than ERAP1 are also present in the serum to maintain homeostasis during the LPS-mediated inflammatory process. We then compared the NO synthetic activities of wild-type and ERAP-knockout mice by measuring the serum NO2−/NO3− content (Fig. 2C). Before LPS injection, comparable NO synthetic activities were detected in the sera of either wild-type or knockout mice. Twelve hours after injection, NO synthetic activities increased in both wild-type and knockout mice. However, while a 4-fold increase was observed in the wild-type mice, only one and a half-fold increase was detected in the ERAP1-knockout mice. At 24 h, the NO synthetic activities of both mice decreased below the basal level, suggesting that LPS injection induces a temporal increase in NO synthesis, and a significant part of this increase is attributable to ERAP1. These results suggest that secreted ERAP1 modulates LPS-mediated NO synthesis. Characterization of NO synthetic activity in LPS-injected mice We then aimed to elucidate the mechanism of ERAP1-mediated increase in NO synthesis. Several reports have shown that inducible nitric oxide synthase (iNOS) plays a dominant role in LPS-dependent NO synthesis in vivo (40, 41). Hence, we examined the effects of LPS injection on the expression of iNOS in the livers of wild-type and ERAP1-knockout mice. iNOS mRNA levels significantly increased in both wild-type and ERAP1-knockout mice 8 h after LPS injection (Fig. 3). At 24 h, iNOS mRNA levels decreased in parallel, although a small but non-negligible level of the mRNAs was still detected. These results indicate that ERAP1 does not affect iNOS mRNA induction, during LPS-mediated inflammation. It has been reported that constitutive NOS (cNOS) contributes to the LPS-dependent NO synthesis via modulation of iNOS expression (42–44). Since we did not detect a difference in LPS-induced expression of iNOS mRNA between wild-type and ERAP1-knockout mice, we concluded that the contribution of cNOS on the ERAP1-mediated iNOS induction was marginal, if any. Fig. 3 View largeDownload slide Role of ERAP1 on the LPS-mediated generation of iNOS mRNA. Wild-type (open bars) and ERAP1-knockout (closed bars) mice were injected LPS intraperitoneally at indicated times. Livers were collected from mice, total RNA was extracted, and cDNA was synthesized. Quantitative real-time PCR was performed to detect the iNOS expression, using the cDNA as a template. Fig. 3 View largeDownload slide Role of ERAP1 on the LPS-mediated generation of iNOS mRNA. Wild-type (open bars) and ERAP1-knockout (closed bars) mice were injected LPS intraperitoneally at indicated times. Livers were collected from mice, total RNA was extracted, and cDNA was synthesized. Quantitative real-time PCR was performed to detect the iNOS expression, using the cDNA as a template. Since NO synthesis requires free arginine (45, 46), we next sought to examine the serum levels of leucine, proline and arginine in wild-type and ERAP1-knockout mice to determine role of ERAP1 in NO synthesis. In our previous study, we hypothesized that the ERAP1-mediated cleavage of N-terminal arginine of substrate peptides is critical for optimum NO synthesis during infectious/inflammatory processes (14). Serum levels of leucine and proline in both wild-type and ERAP1-knockout mice showed no significant statistical difference at any time points after LPS injection (Fig. 4A and B), suggesting constant regulation of both amino acids. In contrast, 24 h after the injection, serum levels of free arginine were consistently higher in wild-type mice when compared to ERAP1-knockout mice. This suggests the role of secreted ERAP1 in increasing the cleavage of substrate peptides with N-terminal arginine and elevating the serum content of free arginine (Fig. 4C). Considering that a significant level of free arginine was also detected in the serum of ERAP1-knockout mice, it is tempting to speculate that secreted ERAP1 in wild-type mice contributes in the increase in concentration of free arginine in a specific area of the blood vessel to locally enhance NO synthesis. Fig. 4 View largeDownload slide Effect of LPS injection on serum concentrations of free amino acids. Sera were collected from wild-type (open bars) and ERAP1-knockout (closed bars) mice, at the indicated times after LPS injection. (A–C) Serum concentrations of free (A) leucine, (B) proline and (C) arginine were measured. Fig. 4 View largeDownload slide Effect of LPS injection on serum concentrations of free amino acids. Sera were collected from wild-type (open bars) and ERAP1-knockout (closed bars) mice, at the indicated times after LPS injection. (A–C) Serum concentrations of free (A) leucine, (B) proline and (C) arginine were measured. Arginine paradox is the phenomenon in which despite the presence of a sufficient intracellular arginine pool, iNOS-mediated NO synthesis is predominantly controlled by extracellular arginine both in vivo and in vitro (14, 46–48). It is thus conceivable that the arginine released by secreted ERAP1 was consumed in NO production. Twelve hours after LPS injection, ERAP1 was secreted into the serum and enhanced the cleavage of N-terminal arginine of putative peptide substrates (such as angiotensin III) in wild-type mice. At the same time, increased iNOS consumed arginine to synthesize NO, resulting in the enhancement of the total synthesis in wild-type mice. As a result, no significant difference in free arginine levels was observed between wild-type and ERAP1-knockout mice 12 h after injection. At 24 h post LPS injection, while secreted ERAP1 levels peaked in the serum, iNOS expression level had declined. Therefore, it is conceivable that free arginine released by ERAP1 accumulated in the serum. In a previous in vitro study, we reported that secreted ERAP1 facilitates NO synthesis in macrophages in an angiotensin III-dependent manner (14). However, it is possible that cell types other than macrophages may also secrete ERAP1. Further studies are required to identify other cell types that secrete ERAP1. It is also important to identify the putative serum peptide substrates of ERAP1 other than angiotensin III. In this study, we examined the role of ERAP1 in NO synthesis in vivo. We found that LPS injection induced the secretion of ERAP1 into the blood, which consequently enhanced NO synthesis, presumably by elevating the serum free arginine level (Fig. 5). During infectious/inflammatory processes, ERAP1 is secreted into blood to cleave peptides containing N-terminal arginine. The released arginine is then used as a substrate by iNOS to synthesize NO. Fig. 5 View largeDownload slide ERAP1 as an acute-phase protein. Schematic representation of the role of secreted ERAP1 in the enhancement of NO synthesis. Fig. 5 View largeDownload slide ERAP1 as an acute-phase protein. Schematic representation of the role of secreted ERAP1 in the enhancement of NO synthesis. ERAP1 is reported to have important roles in the host defense processes, including the modulation of macrophage and NK cell functions, enhancement of NO synthesis, and regulation of blood pressure (5, 13, 14, 16, 49, 50). As ERAP1 is secreted into the blood during the early phases of LPS-induced inflammatory process, it fulfils the properties of acute-phase proteins. Funding This work was supported in part by JSPS KAKENHI (16K08630). Conflict of Interest None declared. References 1 Tsujimoto M. , Hattori A. ( 2005 ) The oxytocinase subfamily of M1 aminopeptidases . Biochim. Biophys. Acta 1751 , 9 – 18 Google Scholar Crossref Search ADS PubMed 2 Hattori A. , Tsujimoto M. 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TI - Acute-phase protein-like properties of endoplasmic reticulum aminopeptidase 1
JF - The Journal of Biochemistry
DO - 10.1093/jb/mvy090
DA - 2019-02-01
UR - https://www.deepdyve.com/lp/oxford-university-press/acute-phase-protein-like-properties-of-endoplasmic-reticulum-PiJcTT0bBP
SP - 159
VL - 165
IS - 2
DP - DeepDyve
ER -