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INFLAMMATION/IMMUNITY/MEDIATORS

Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis

¹Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas; and ²Department of Molecular and Integrative Physiology and ³Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan

Submitted 7 October 2005 ; accepted in final form 1 March 2006

	ABSTRACT

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Endoplasmic reticulum (ER) stress mechanisms have been found to play critical roles in a number of diseases states, such as diabetes mellitus and Alzheimer disease, but whether they are involved in acute pancreatitis is unknown. Here we show for the first time that all major ER stress sensing and signaling mechanisms are present in exocrine acini and are activated early in the arginine model of experimental acute pancreatitis. Pancreatitis was induced in rats by intraperitoneal injection of 4.0 g/kg body wt arginine. Pancreatitis severity was assessed by analysis of serum amylase, pancreatic trypsin activity, water content, and histology. ER stress-related molecules PERK, eIF2, ATF6, XBP-1, BiP, CHOP, and caspase-12 were analyzed. Arginine treatment induced rapid and severe pancreatitis, as indicated by increased serum amylase, pancreatic tissue edema, and acinar cell damage within 4 h. Arginine treatment also caused an early activation of ER stress, as indicated by phosphorylation of PERK and its downstream target eIF2, ATF6 translocation into the nucleus (within 1 h), and upregulation of BiP (within 4 h). XBP-1 splicing and CHOP expression were observed within 8 h. After 24 h, increased activation of the ER stress-related proapoptotic molecule caspase-12 was observed along with an increase in caspase-3 activity and TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL) staining in exocrine acini. These results indicate that ER stress is an important early acinar cell event that likely contributes to the development of acute pancreatitis in the arginine model.

pancreas; apoptosis

Disturbances of ER function lead to a well-identified series of ER stress response mechanisms (7, 20). One of the major reactions of the ER to stress is the unfolded protein response (UPR). The UPR couples the ER protein load with the ER protein folding capacity. It is sensitive to a variety of perturbations, including oxidative stress, Ca²⁺ imbalance, and mutant proteins that do not fold properly, all of which lead to an accumulation of misfolded proteins (23). Key components of the UPR in mammals include three different ER stress transducers localized to the ER membrane, which are constitutively expressed in all cells and activated during ER stress: PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-required enzyme 1 (IRE1) (7, 20). PERK activation involves autophosphorylation and leads to the subsequent phosphorylation of eukaryotic initiation factor 2 alpha (eIF2) and, consequently, a general decrease in translation initiation (8, 16). Activation of ATF6 leads to increased transcription of ER chaperones, including BiP (also called GRP78), and protein folding enzymes that help alleviate the stress (28, 35). Activation of IRE1 causes splicing and activation of the transcription factor XBP-1 that is also involved in gene expression of different chaperones and foldases that relieve ER stress (4). However, if the overload of misfolded proteins in the ER is not resolved, then prolonged activation of UPR leads to programmed cell death. This effect is mediated in part by increased expression of the transcription factor C/EBP homologous protein (CHOP, also called growth arrest and DNA damage inducible gene 153, GADD153), which leads to decreased Bcl-2 protein (18). A second proapoptotic pathway emanating from the ER involves the ER initiator procaspase-12, which is activated by cleavage under ER stress conditions and then can activate caspases-9 and -3, leading to apoptosis (21, 22).

In the current study, we investigated for the first time the presence and activation of ER stress-related mechanisms in acute pancreatitis using the arginine model. We observed the activation of all major components of the UPR at early time points in the development of the disease simultaneously with pathological alterations. Together, these data indicate that ER stress mechanisms are present in exocrine acini and are activated early in the arginine model of acute pancreatitis.

	METHODS

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Induction of acute pancreatitis. Male Wistar rats (Harlan, Indianapolis, IN), weighing 150–200 g, had ad libitum access to regular laboratory chow and water and were housed at 24°C on a 12:12-h light-dark cycle. In each experimental group three or four animals were used. After overnight fasting, rats received a single intaperitoneal injection of 4.0 g/kg body wt L-arginine (Sigma-Aldrich, St. Louis, MO) in saline (pH 4.0) into the left lower abdomen. Rats were euthanized in a CO₂ chamber after 1, 4, 8, 24, and 72 h. The local Animal Care and Use Committees (University of Michigan and University of Texas, MDACC) approved all animal experimental protocols. Rats were treated according to the Guiding Principles in the Care and Use of Animals.

Evaluation of arginine-induced injuries. Mixed arterial-venous blood and pancreatic tissue were collected and processed as described (14). Serum amylase activity was measured by a Phadebas test (Pharmacia Diagnostics, Uppsala, Sweden). The extent of pancreatic edema was determined by measuring tissue water content (wet weight – dry weight/wet weight x 100 = percent tissue water content).

Quantification of pancreatic trypsin activity. Tissue samples were homogenized in MOPS buffer. The homogenate was centrifuged at 3,000 rpm for 5 min, and the supernatant was used for the assay. Trypsin activity was either measured fluorometrically using Boc-Glu-Ala-Arg-AMC-HCl (Bachem Bioscience, King of Prussia, PA) according to the method of Kawabata et al. (13) or chromogenically using Z-Gly-Pro-Arg p-nitroanilide acetate (Sigma-Aldrich) as a substrate, according to Chen et al. (5), with similar results. Concentrations were calculated using standards generated by purified trypsin (Sigma-Aldrich). Protein concentrations of each sample were determined (Bio-Rad Laboratories, Hercules, CA), and trypsin activity was expressed as nanograms per milligram protein.

Evaluation of pancreatic morphology and immunohistochemistry. Tissue samples were fixed overnight in fresh 4% formaldehyde in phosphate-buffered saline (PBS) and embedded in paraffin. Four-micrometer sections were prepared and stained with haematoxylin and eosin (H&E) for morphological examination. Active caspase-3 was localized in deparaffinized sections with a rabbit monoclonal antibody to the active fragment of caspase-3 (no. 59565; BD PharMingen, San Diego, CA), using a Vectastain immunoperoxidase ABC kit and Vectastain DAB peroxidase substrate kit (both from Vector Laboratories, Burlingame, CA). Sections were pretreated for 15–30 min with 0.3% H₂O₂ in distilled water to block endogenous peroxidase before incubation with a 1:500 dilution of primary antibody for 90 min. TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL) detection of DNA fragmentation was carried out using a peroxidase-based detection kit (Roche Applied Science, Indianapolis, IN). Sections, pretreated to block endogenous peroxidase, were permeabilized with 20 µg proteinase K in 10 mM Tris·HCl buffer, pH 7.4 (nuclease free, Roche), before TUNEL localization following the manufacturer's directions. Slides were viewed with an Olympus BX-51 light microscope (Olympus America, Melville, NY). All images were recorded digitally and processed using Adobe Photoshop 6.0 software (Adobe, Mountain View, CA).

RT-PCR. Standard RT-PCR was performed using total RNA from arginine-treated and control pancreatic tissue. RT was conducted for 45 min at 42°C from 1 µg of RNA by using avian myeloblastosis virus reverse transcriptase (Promega, Madison, WI). One microliter of RT products was used in standard PCR with PCR mastermix (Promega). Amplified products were separated on agarose gels, visualized by ethidium bromide staining, and verified by sequencing. Specific primers were used for CHOP (GenBank acc. no. NM024134) (forward, 5'-AGG AGC CAG GGC CAG CAG AGG T-3'; reverse, 5'-ATC AGA GCC CGC CGT GTG GTC-3') and for the selective amplification of the splice variant of XBP-1 (sXBP-1) (GenBank acc. no. AF443192) (forward, 5'-GAG TCC GCA GCA GGT G-3'; reverse, 5'-GTG TCA GAG TCC ATG GGA-3'). Ribosomal 18S RNA served as the internal loading control (forward, 5'-GAG CGG TCG GCG TCC CCC AAC-3'; reverse, 5'-GCG CGT GCA GCC CCG GAC ATC-3').

Western blotting. Whole cell lysates were prepared from pancreatic tissues (14). Protein concentration was determined (Bio-Rad Laboratories), and 12–30 µg of protein were mixed with sample loading buffer according to the procedure of Laemmli (15). PAGE was performed using Tris·HCl ready gels (Bio-Rad Laboratories). Separated proteins were blotted on nitrocellulose membranes (Amersham Biosciences, Buckinghamshire, UK). After blocking for 1 h, the following antibodies were used: anti-total-eIF2 (no. 9722; Cell Signaling Technology, Beverly, MA), anti-phospho-eIF2 (Ser51) (no. KAP-CP130) and anti-BiP (no. SPA-826; Stressgen, Victoria, Canada), anti-phospho-PERK (Thr981) (sc-32577-R), anti-ATF6 (sc-22799), anti-sXBP-1 (sc-7160; Santa Cruz Biotechnology, Santa Cruz, CA), and anti-GADD153/CHOP (G 6916), and anti-caspase-12 (C 7611, Sigma-Aldrich). Anti-actin antibody (A-2066, Sigma-Aldrich) was used to measure actin as an internal loading control. Membranes were incubated with the appropriate IgG secondary antibody conjugated either with horseradish peroxidase (Amersham Biosciences) or a fluorescent Alexa Fluor secondary antibody (Molecular Probes, Eugene, OR). Antibody binding was detected by enhanced chemiluminescence (Pierce, Rockford, IL), recorded on X-ray films or with the LI-COR Odyssey infrared imager. Membranes were scanned, recorded digitally, and processed using Quantity One (Bio-Rad Laboratories).

Statistical analysis. The Student t-test was used to investigate the difference of each parameter. The results were regarded as significantly different when the P value was <0.05. Values are means ± SE.

	RESULTS

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Arginine treatment induces rapid pancreatitis. Arginine treatment leads to a rapid induction of acute pancreatitis, as previously reported by others (9, 19, 33). In the current study, several biochemical parameters were measured to assess the pancreatitis severity. An early and significant twofold increase in serum amylase after 4 and 8 h was detected in arginine-treated rats (Fig. 1, A.1). These effects were transient and returned to control values after 24 and 72 h. An identical pattern was observed in the measurement of edema with a significant elevation in pancreatic water content at 4 and 8 h after arginine treatment, which was resolved within 24 h (Fig. 1, A.3). In contrast, arginine treatment did not increase trypsin activity in pancreatic tissue before 24 h, where a sevenfold increase in trypsin activity was measured in samples from pancreatitis rats (Fig. 1, A.2). Arginine treatment also induced NFB activation as has been reported previously (24) (data not shown).

View larger version (65K): [in this window] [in a new window]   Fig. 1. L-Arginine treatment induces rapid pathophysiological changes in the pancreas. Rats were treated with a single intraperitoneal injection of saline or L-arginine and killed after 1, 4, 8, 24, and 72 h. A: biochemical measurements indicate the induction of acute pancreatitis after arginine treatment: amylase (A.1), edema (A.2), and trypsin (A.3) activity. Values are means ± SE, *P < 0.05, n = 3 or 4. B.1–B.7: histological changes indicated the development of acute pancreatitis after arginine treatments. Images represent pancreatic histology at indicated times after arginine treatment.

Arginine treatment causes rapid induction of ER stress mechanisms. ER stress-related mechanisms were evaluated at various times after arginine treatment. An early marker of ER stress is the activation by autophosphorylation of the ER-resident kinase and stress sensor PERK. Phosphorylation of PERK was increased after 1 h, reached a maximum at 24 h (268 ± 11% of control, P < 0.01) after arginine treatment (Fig. 2, A and B). The major downstream target of PERK is eIF2, which controls general protein translation. Phosphorylation of eIF2, which reduces translation initiation, was apparent 4 h after arginine treatment and remained above control until at least 72 h (Fig. 2C). Basal levels of phosphorylated eIF2 were detected in all saline control animals without any change over time. Western blotting for total eIF2 demonstrated equal protein loading (Fig. 2C, bottom).

View larger version (24K): [in this window] [in a new window]   Fig. 2. The ER stress sensor PERK and eIF2 are rapidly phosphorylated after arginine administration. Rats were treated with saline or L-arginine and killed after 1, 4, 8, 24, and 72 h. A: phospho-PERK was detected by Western blotting with a phospho-specific antibody. Phospho-PERK levels were elevated after 1 h and remained above control for at least 24 h after arginine treatment. B: quantification of Western blots revealed a maximum phosphorylation of PERK at 24 h. Values are means ± SE, *P < 0.05, n = 3. C: phosphorylation of eIF2 was detected by Western blotting with a phospho-specific antibody. Phosphorylation of eIF2 was increased after 4 h and remained above control for at least 72 h after arginine treatment (top). Western blotting with an anti-total eIF2 antibody demonstrated equal protein loading (bottom).

View larger version (34K): [in this window] [in a new window]   Fig. 3. ER stress-related alterations in ATF6, BiP, and sXBP-1 are observed after arginine treatment. Rats were treated with saline or L-arginine and killed after 1, 4, 8, 24, and 72 h. A: the posttranslational transfer of ATF6 from the endoplasmic reticulum (ER) membrane into the nucleus was analyzed in different cell fractions at indicated times after treatment with arginine or saline controls. ATF6 was detected in the cytoplasm prepared from control pancreata at all times. However, ATF6 levels were undetectable in the nuclear fraction prepared from controls. In contrast, within 4 h after arginine treatment, ATF6 appeared in the nucleus, and ATF6 disappeared almost completely from the cytoplasm after 8 h. Western blot against actin showed equal protein loading in the cytoplasmic fraction. B: levels of the ER-resident chaperone BiP were measured by Western blotting after arginine treatment. BiP was present in all cell lysates, but the levels were increased in pancreatic tissue lysates after L-arginine treatment beginning after 4 h and continuing for at least 72 h. The bottom shows an actin Western blot as a protein loading control. C: the posttranslational processing of XBP-1 into its active form sXBP-1 was examined by RT-PCR specifically designed for sXBP-1 after arginine treatment. sXBP-1 was constitutive expressed in all control pancreata, and its levels were increased after 4 h and peaked 24 h after arginine administration. RT-PCR of ribosomal 18S RNA was used to indicate equal sample loading. D: Western blotting revealed an increase of sXBP-1 protein in the pancreas within 8 h after arginine injection, which lasted at least for 72 h. Western blotting for actin was used to verify equal protein loading. E: quantification of data from sXBP-1 Western blotting indicated significantly increased levels at 8 h and up to 72 h after arginine treatment. Values are means ± SE, *P < 0.05, n = 3.

Arginine treatment activates ER stress-related apoptotic mechanisms. Next we investigated proapoptotic ER stress pathways that are activated upon prolonged stress. Western blotting for the ER-resident procaspase-12 showed cleavage of this initiator procaspase within 8 h, extending to at least 24 h after arginine administration (Fig. 4A). Immunohistochemical analysis indicated the induction of active caspase-3, which is describe as a downstream target of caspase-12, within 24 h after arginine injection (Fig. 4B, left). TUNEL staining of the same specimens revealed a positive signal at 24 h after arginine administration, indicating acinar cell death at this time point (Fig. 4B, left and right). We also analyzed the transcriptional upregulation of CHOP, which is downstream of several ER stress sensors. CHOP mRNA levels were increased in L-arginine-treated rats starting at 4 h with a peak after 24 h (Fig. 4C, top). Western blotting for CHOP showed an increase in protein levels after 8 and 24 h (Fig. 4C, bottom).

View larger version (63K): [in this window] [in a new window]   Fig. 4. Arginine treatment activates the apoptotic mechanisms caspase-12, caspase-3, and CHOP. Rats were treated with saline or L-arginine and killed after 1, 4, 8, 24, and 72 h. A: Western blotting using an antibody for caspase-12 revealed a loss of the procaspase-12 band at a molecular mass of 50 kDa, indicating cleavage of the initiator procaspase within 8 h of arginine treatment. Starting at 8 h after arginine administration, a lower molecular mass band of 20 kDa appeared, corresponding to the cleaved activated caspase-12. B: arginine administration also induced active effector caspase-3 by 24 h, as indicated by immunohistochemical analysis with an antibody specific for active caspase-3 (left). Sections of the same specimens were stained for TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL) and are displayed on the right. TUNEL staining was observed within 24 h after arginine administration, indicating an acinar cell undergoing apoptosis. C: CHOP mRNA levels were elevated within 4 h of arginine administration with a peak observed after 24 h. RT-PCR of ribosomal 18S RNA was used to indicate equal sample loading. The bottom shows CHOP protein levels. Arginine treatment increased CHOP protein levels after 8 and 24 h. The anti-actin Western blot underneath was used as loading control.

	DISCUSSION

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ER stress influences cell function at a variety of levels including gene transcription and translation. Activation of the ER-resident kinase PERK is particularly important for effects on translation, as one of its major targets is the translation initiation factor eIF2. Phosphorylation of eIF2 leads to a reduction in the rate of general protein synthesis. We found that PERK was rapidly activated, and eIF2 was phosphorylated within 4 h of arginine treatment. This finding is in accordance with the observation made previously that eIF2 phosphorylation and protein synthesis inhibition occurs in pancreatitis induced by high concentrations of caerulein in mice (26). In addition to PERK, three other mammalian eIF2 kinases have been described (12). Each of these kinases senses stress signals and activates downstream response pathways by regulating cellular translation. These eIF2 kinases include GCN2, which is activated by nutritional stress; HRI, which links protein synthesis to heme availability and is also activated by oxidative and heat stress; and PKR, which is induced by interferon. In our study we focused on the activation of PERK, which occurred early and paralleled the early increase in eiF2 phosphorylation. However, the activation of other kinases, especially at later times, may help explain the observation in the current study of prolonged eIF2 phosphorylation despite a decrease in PERK phosphorylation after 72 h. Further studies will be necessary to evaluate the roles of additional mechanisms.

In contrast to its effects on general protein synthesis, inhibition of eIF2 leads to increased translation of a particular subset of mRNAs that includes important ER stress-related genes and transcription factors (17). Among the transcription factors regulated by PERK phosphorylation of eIF2 is ATF3 (11). We previously reported that ATF3 levels are increased early in pancreatitis induced by either caerulein or intraductal administration of taurocholate (10), and ATF3 levels were also elevated by arginine (unpublished data). Therefore, ER stress influences pancreatic acinar cell function by influencing both translation and transcription of key regulators in distinct experimental models.

After treatment with arginine, we also noted a rapid activation of the other major ER stress molecules ATF6 and IRE1. ATF6, an integral element of the UPR, is released from the ER membrane and translocates to the Golgi apparatus upon dissociation from BiP. Within the Golgi, ATF6 undergoes sequential proteolytic cleavage by the proteases S1P and S2P, yielding a free 50-kDa cytoplasmic domain as an active transcription factor for ER stress target genes (35). IRE1 is a stress sensor that undergoes oligomerization and autophosphorylation of its kinase domain upon the dissociation of BiP. These effects lead to activation of a COOH-terminal endonuclease domain of IRE1, which catalyzes the removal of a small (26 nucleotides) intron from XBP-1 mRNA. The splicing event creates a translational frameshift in XBP-1 mRNA to produce an active transcription factor sXBP-1. sXBP-1 binds to the ER stress-specific response element in the promoter region of a variety of molecular chaperones and other ER stress-regulated genes (16). In our study we observed an increase in the constitutive expression level of sXBP-1 after L-arginine treatment, indicating the activation of IRE1. Thus all three major ER stress mechanisms were rapidly activated in the pancreas of rats following arginine treatment.

The mechanisms involved in the induction of ER stress by arginine are not completely understood. However, it is known that arginine treatment causes oxidative stress in the pancreas (6, 34), and oxidative imbalance induces ER stress (29). Reduction of oxidative stress has previously been found to reduce the severity of acute pancreatitis, but the mechanisms that explain the role of oxidative stress in acute pancreatitis have not been clear (27). The current results suggest that ER stress may be a common consequence of oxidative stress leading to changes in gene expression and activation of the cellular processes that result in acute pancreatitis. This hypothesis is supported by experiments using antioxidants that reduce both ER stress and the severity of acute pancreatitis (unpublished observations). However, it also remains possible that ER stress and the severity of pancreatitis are independently influenced by oxidative imbalance. Furthermore, research will be necessary to fully understand the relationship between oxidative stress, ER stress, and severity of acute pancreatitis.

Based on what is known from other systems, it seems likely that under normal conditions ER stress mechanisms would play primarily a protective role by induction of chaperones, antioxidants, and other protective molecules. Simultaneous increases in both protective and proinflammatory and proapoptotic genes have previously been noted in profiling studies of acute pancreatitis (10). In the current study we observed a rapid and dramatic increase in the level of BiP, an ER-specific member of the heat shock HSP70 family of molecular chaperones. It has long been observed that heat shock proteins are induced during acute pancreatitis, but the significance of this observation linking acute pancreatitis to ER stress has not previously been noted. More importantly, previous induction and overexpression of heat shock proteins has been found to prevent or reduce the severity of subsequent pancreatitis (3, 32). The explanation for this effect of HSPs has not been completely understood. HSPs have previously been found to reduce or prevent ER stress-related cell damage and apoptosis in other systems (2). Our data suggest that increased HSPs may reduce subsequent ER stress and thereby reduce the alterations in cytokine and chemokine gene expression that lead to many of the systemic aspects of the disease. Further studies will be necessary to investigate this suggestion.

Severe or prolonged ER stress leads to cell damage that plays a critical role in several important diseases including diabetes, ₁-antitrypsin deficiency, and Alzheimer disease (1). In the current study we show that specific ER stress-related apoptotic pathways are activated after arginine treatment. The ER-resident procaspase-12 is an ER stress-specific proapoptotic molecule (22). Procaspase-12 gets cleaved and can sequentially lead to the activation of the downstream effector caspase-3. We observed that procaspase-12 and the downstream caspase-3 are activated after arginine treatment and confirmed acinar cell death with a positive TUNEL staining. Another ER stress-related proapoptotic mechanism involves induction of the transcription factor CHOP, which is regulated by all three ER stress sensors PERK, IRE1, and ATF6. We observed an increase of CHOP mRNA and protein levels after arginine administration. These data support the conclusion that arginine treatment leads to the activation of ER stress mechanisms and further indicate that this stress is severe and prolonged. The specific role of apoptosis in acute pancreatitis is currently under discussion, but these data suggest that ER stress-regulated mechanisms are likely involved in the apoptosis observed in this model of the disease.

In conclusion, we have demonstrated for the first time that ER stress signaling pathways are activated early in the course of acute pancreatitis and correlate with the severity of the disease using the arginine model. Based on the significance of ER stress mechanisms in several other diseases, these mechanisms are likely to also be salient in acute pancreatitis, and understanding their role in this disease will have important implications for the design of future treatments.

	GRANTS

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This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-52067 (to C. D. Logsdon) and DK-59578 (to J. A. Williams), the Michigan Gastrointestinal Peptide Center, Grant DK-34933, and the Lockton Endowment.

	ACKNOWLEDGMENTS

 
We are grateful to Bradley B. Nelson for assistance with immunocytochemistry.

	FOOTNOTES

 

Address for reprint requests and other correspondence: C. D. Logsdon, Dept. of Cancer Biology, Unit 953, Univ. of Texas, M.D. Anderson Cancer Center, SCR2.2014, 7435 Fannin St., Houston, TX 77230-1429 (e-mail: clogsdon{at}mdanderson.org)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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