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Xiaozhong Wang,6,
Wendy L. Frankel,7 Denis Guttridge,8 Marc Prentki,5 Shane T. Grey,9 David Ron,6 and Tsonwin Hai1,2*
Department of Molecular and Cellular Biochemistry,1 Center for Molecular Neurobiology,2 Department of Veterinary Biosciences,3 Department of Molecular Virology, Immunology, and Medical Genetics,8 Department of Pathology, Ohio State University, Columbus, Ohio,7 Immunology Research Center, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, Massachusetts,4 Department of Nutrition, University of Montreal, Montreal, Quebec, Canada,5 Skirball Institute, NYU School of Medicine, New York, New York,6 Arthritis and Inflammation Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia9
Received 30 March 2004/ Accepted 1 April 2004
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ABSTRACT |
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B and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in ß cells develop abnormal islets and defects secondary to ß-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced ß-cell apoptosis. |
INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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], and gamma interferon [IFN-
]) destroy ß cells in the islets of Langerhans, leading to the pathogenesis of type 1 diabetes (11, 14, 15, 42); on the other hand, elevated glucose and free fatty acids (FFAs)—common metabolic abnormalities in type 2 diabetes—induce ß-cell death, contributing to the progression of the disease (13, 32, 35, 53, 62). Emerging evidence indicates that activation of the NF-B and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathways is a key event leading to cell death, when ß cells are exposed to these signals: proinflammatory cytokines, elevated glucose, and elevated FFAs (12, 15, 16, 43, 49). Furthermore, activation of these pathways has been demonstrated to impair insulin signaling (1, 17, 18, 36) and play a role in type 2 diabetes (63, 71). Therefore, these stress-activated signaling pathways constitute a common molecular mechanism in the pathophysiological progression of type 1 and type 2 diabetes. Thus far, inducible nitric oxide (NO) synthase (iNOS), whose expression leads to NO production, is one of the best known target genes for these pathways (14-16, 42, 54). Several lines of evidence indicate that iNOS plays an important role in the pathogenesis of diabetes. (i) iNOS is induced in the islets by cytokines (16) and is expressed in the islets of diabetes prone BB rats (33) and nonobese diabetic (NOD) mice (55, 58). (ii) Transgenic mice expressing iNOS in ß cells develop ß-cell destruction and diabetes (60). (iii) ß cells lacking functional iNOS are partially protected from stress-induced cell death (19, 41, 59).
In this report, we demonstrate that activating transcription factor 3 (ATF3), another stress-inducible gene, may be a downstream target of the NF-B and JNK/SAPK signaling pathways and may play a role in ß-cell apoptosis. ATF3 encodes a member of the ATF/CREB family of transcription factors (24, 26), and its expression is induced in a variety of tissues by different stress signals (for reviews, see references 25 and 27), including in the brain by seizure; in the liver by carbon tetrachloride; and in the pancreas, heart, and kidney by ischemia coupled with reperfusion (ischemia-reperfusion). Importantly, the induction of ATF3 correlates with cellular damage: all signals that induce ATF3 also induce cellular damage, and signals that do not induce ATF3 do not induce damage (25, 27). However, the functional significance of ATF3 is not clear. To date, both protective and detrimental effects of ATF3 expression have been reported. In cardiac myocytes, ectopic expression of ATF3 by adenoviral vector inhibited adriamycin-induced apoptosis (47), indicating a protective role of ATF3. Consistently, adenovirus-mediated expression of ATF3 protected superior cervical ganglion neurons from nerve growth factor withdrawal-induced apoptosis (46). However, in HeLa cells ectopic expression of ATF3 enhanced the ability of etoposide or camptothecin to induce apoptosis (44), suggesting a proapoptotic role of ATF3. Consistent with the proapoptotic role of ATF3, transgenic mice expressing ATF3 have functional defects in the corresponding tissues: mice expressing ATF3 in the heart have conduction abnormalities and contractile dysfunction (48); mice expressing ATF3 in the liver and pancreatic ductal epithelium have liver dysfunction and defects in endocrine pancreas development (2, 3). Therefore, the physiological function of ATF3 has been suggested to be either protective or detrimental. To address this controversy, we took both loss-of-function and gain-of-function approaches. In this report, we describe the generation of knockout mice deficient in ATF3 and transgenic mice expressing ATF3 specifically in ß cells. Our results suggested ATF3 to be a stress-inducible, proapoptotic gene in ß cells.
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MATERIALS AND METHODS |
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, or IFN- (1,000 U/ml each), or in combination (R&D Systems); (ii) bovine serum albumin (BSA) alone (0.5%) or BSA coupled with palmitate (0.4 mM) as detailed elsewhere (56); and (iii) 0.05 to 0.5 mM S-nitroso glutathione (GSNO) (Calbiochem). For inhibitors, cells were incubated with 20 µM Bay11-7082 or Bay11-7085 (Biomol), NF-B SN50 or NF-B SN50 M (4 µg/ml; Biomol), or 5 µM (unless otherwise indicated) JNKI-1 (Cleveland Clinic Foundation) for 30 min prior to IL-1ß treatment. Enzyme-linked immunosorbent assay (ELISA) analysis of DNA fragmentation. DNA fragments were quantified at 24 h after glucose or palmitate treatment using the Cell Death Detection ELISA Plus Kit (Roche), which allows the determination of mono- and oligonucleosomes generated by apoptotic cleavage of DNA. The amount of nucleosomes (quantified photometrically by peroxidase activities) was determined on a FLUOstar Optima microplate reader (BMG) at 405 nm.
RNA isolation, real-time PCR, immunoblot, and immunohistochemistry. Total RNA was isolated at 1 h after treatment unless otherwise indicated, and ATF3 or glyceraldehyde-3-phosphate dehydrogenase mRNA analyzed by real-time PCR as previously (2). Nuclear extracts were isolated at 1 h after treatment unless otherwise indicated, and equal amount of extract was analyzed by immunoblot using anti-ATF3 (Santa Cruz), antiactin (Sigma), or anti-extracellular signal-regulated kinase (anti-ERK) (Cell Signaling Technology) antibodies. Immunohistochemistry was determined as previously described (2). Human pancreata were retrieved from the archival files at Ohio State University. Only cases with minimal autolysis were used. The diagnoses of diabetes (type 1 or 2) were based on the medical records.
Analyses of JNK/SAPK, p38, and NF-B activity.
JNK/SAPK was immunoprecipitated from INS832/13 cell extract at 30 min after IL-1-ß treatment, and assayed using glutathione S-transferase-Jun(1 to 79 amino acids) as substrate in the absence or presence of indicated inhibitors. p38 activation was assayed by the phosphorylation of its substrate ATF2 using phospho-specific antibody (Cell Signaling). NF-B activity was determined by electrophoretic mobility shift assay (EMSA) as previously described (23).
Generation of PDX-ATF3 transgenic mice. A 1.0-kb enhancer region (kb –2.7 to –1.7) of the PDX promoter (C. Wright at Vanderbilt University) was inserted upstream of the E1B TATA box to drive the expression of ATF3 as shown (see Fig. 4). Transgenic mice were generated in FVB/N mice and identified by PCR.
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Generation and confirmation of ATF3 knockout mice. ATF3 genomic clone was isolated from a 129SVJ library and knockout mice were generated in the 129SVJ background. Knockout allele was distinguished from the wild-type allele by Southern blot or PCR. For Southern blot, genomic DNA was digested by EcoRV and analyzed by a 5' probe (EcoRI-XhoI fragment) (see Fig. 3 and Fig. S1 in the supplemental material), or digested by EcoRI and analyzed by a 3' probe (BglII fragment) (see Fig. 3a and Fig. S1 in the supplemental material). For PCR, three primers were used: 5'-AGAGCTTCAGCAATGGTTTGC-3' (primer 1), 5'-TGAAGAAGGTAAACACACCGTG-3' (primer 2), and 5'-ATCAGCAGCCTCTGTTCCAC-3' (primer 3). Congenic knockout mice in the background of C57BL/6 were generated by 10 backcrosses. Wild-type or knockout mice were injected with lipopolysaccharide (LPS) at 1.5 mg/kg of body weight (i.p.) or phosphate-buffered saline as a control. At 4 h after treatment, mice were sacrificed and nuclear extract from liver was analyzed by immunoblotting.
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(200 U/ml), TNF- (200 U/ml), anti-Fas monoclonal antibody Jo-2 (2 µg/ml; Pharmingen), or 0.625 mM GSNO. When indicated, L-N5-(1-iminoethyl) ornithine dihydrochloride (L-NIO) was included at 500 µM. For GSNO treatment, NO content in the medium was confirmed by Griess reagent. At 24 h after treatment, islets were dispersed, stained with propidium iodide, and analyzed by flow cytometry for apoptosis as described previously (22). Apoptotic cells were scored as cells with a hypodiploid DNA content (<2N). Cell debris and apoptotic cell-free fragments were excluded by discounting the events with an FL-2 area profile below that of chicken erythrocyte nuclei. Percentage increase in apoptosis (induced by a given treatment) was calculated according to an established method (22, 41): (% apoptotic cells after treatment – % apoptotic cells in medium control) ÷ (100% – % apoptotic cells in medium control). Institutional reviews. Animal experiments and experiments using patient samples were approved by the appropriate Institutional Review Board at Ohio State University.
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RESULTS |
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or IFN- alone did not (not shown). Interestingly, TNF- plus IFN- enhanced and prolonged the induction of ATF3 by IL-1ß (Fig. 1a). Immunoblot analysis confirmed the production of ATF3 protein (Fig. 1b). This TNF--IFN--mediated potentiation parallels the well-documented potentiation of IL-1ß-induced apoptosis by these two cytokines (42), supporting the notion that ATF3 expression contributes to apoptosis (see below). Combinations of two cytokines indicated that IL-1ß-TNF- or IL-1ß-IFN- induced ATF3 at about 70 to 90% efficiency compared to all three cytokines, and TNF--IFN- induced ATF3 at around 10% efficiency (Fig. 1c). Elevated glucose (25 mM), a condition that induced apoptosis in INS832/13 cells (Fig. 1e, bar 3), induced ATF3 around 30-fold (Fig. 1d, bar 3). The fatty acid palmitate (n-hexadecanoate, 16:0), which induced apoptosis modestly (Fig. 1e, bar 2), induced ATF3 by twofold (Fig. 1d, bar 2). Interestingly, glucose plus palmitate (glucolipotoxicity [53]) induced ATF3 and apoptosis with a higher efficiency than either treatment alone (Fig. 1d and e). The induction of ATF3 by palmitate is consistent with the DNA microarray result that ATF3 is induced in MIN-6 ß cells by this fatty acid (7).
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B and JNK/SAPK pathways in the induction of ATF3 by IL-1ß.
As described in the introduction, the NF-B and JNK/SAPK pathways play an important role in ß-cell apoptosis and diabetes. Interestingly, the human ATF3 promoter contains NF-B, AP-1, and ATF/CRE sites (37), binding sites recognized by the transcription factors activated by the NF-B and JNK/SAPK pathways (for a review, see reference 68). These observations, combined with the induction of ATF3 by stress signals in ß cells (above), prompted us to examine whether the activation of these pathways is necessary for the induction of ATF3 by IL-1ß using an inhibitory approach. To inhibit the NF-B pathway, we used two types of reagents: (a) small compound inhibitors of IKK—Bay11-7082 and Bay11-7085 (52), and (b) a cell-permeable peptide NF-B SN50 which blocks the nuclear translocation of NF-B p50 (40). These inhibitors reduced the induction of ATF3 by IL-1ß in INS832/13 cells as indicated by real-time PCR, but a control peptide NF-B SN50 M which contains a mutation in the peptide did not affect ATF3 induction (Fig. 2a). Immunoblot analysis indicated that the inhibitors also reduced the ATF3 protein level (Fig. 2b). EMSA confirmed that Bay11-7082 and Bay11-7085 inhibited the NF-B DNA binding activity in the nuclear extracts (Fig. 2c). However, the inhibitors did not inhibit JNK/SAPK (Fig. 2d) or p38 kinase (Fig. 2e) which is also induced by IL-1ß. To inhibit the JNK/SAPK pathway, we used the JNKI-1 peptide, a cell-permeable peptide that inhibits the activation of this pathway (6). JNKI-1 reduced the induction of ATF3 by IL-1ß at both the mRNA (Fig. 2f) and protein (Fig. 2g) levels. The inhibition at the protein level appears to be more efficient than that at the mRNA level. Further investigation is required to explain this apparent difference. The specificity of the peptide is indicated by its ability to inhibit JNK/SAPK (Fig. 2h), but not NF-B (Fig. 2i) or p38 (Fig. 2j) pathway. Interestingly, combination of both inhibitors (JNKI-1 plus Bay11-7082) did not result in a complete inhibition of ATF3 induction (Fig. 2f), suggesting that other pathways are also involved.
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induced ATF3 in ATF3+/+ islets (Fig. 3d). As expected, ATF3 protein was absent in the ATF3–/– islets after cytokine treatment, further confirming the functional knockout of ATF3 gene. We then treated the islets with cytokines and assayed apoptosis at 24 h after treatment by propidium iodide stain followed by flow cytometry. Results from five experiments indicated that ATF3–/– islets were partially protected from two-cytokine (IL-1ß-IFN-)-induced apoptosis (P < 0.05) but were only marginally protected (not statistically significant) from three-cytokine (IL-1ß-IFN--TNF-)- or two-cytokine-plus-Fas-induced apoptosis (Fig. 3e, right panel). A representative flow cytometry result is shown (left panel).
As shown above, the NF-B and JNK/SAPK pathways play an important role in the induction of ATF3 by IL-1ß. Overwhelming evidence in the literature indicates that these pathways mediate cytokine-induced expression of iNOS (15, 22, 43). Induction of iNOS leads to NO production, and NO donor GSNO is widely used to mimic the action of iNOS. We found that GSNO induced ATF3 in both INS832/13 ß cells (Fig. 3f) and primary islets (Fig. 3g). Interestingly, ATF3–/– islets were partially protected (P < 0.01) from GSNO-induced apoptosis (Fig. 3h). That is, NO in the absence of ATF3 (ATF3–/– background) fails to elicit efficient killing, suggesting that the induction of ATF3 by NO plays a role in NO-induced ß-cell apoptosis. Previously, iNOS–/– islets (ATF3+/+) were shown to be partially protected from cytokine-induced apoptosis (41), indicating that induction of ATF3 (by cytokines) in the absence of iNOS (iNOS–/– background) fails to elicit efficient killing. Taken together, these observations suggest that induction of both ATF3 and iNOS is necessary for stress signals to elicit efficient ß-cell killing. Consistent with this interpretation, iNOS inhibitor L-NIO further decreased two-cytokine-induced apoptosis in ATF3–/– islets (Fig. 3h).
Dysfunction in transgenic mice expressing ATF3 in islets.
To further address the functional significance of ATF3 expression in islets, we took a gain-of-function approach and generated transgenic mice expressing ATF3 under the control of the fragment from kb –2.7 to –1.7 of the PDX-1 promoter (Fig. 4a). This fragment was demonstrated to target transgenes selectively in the developing islets and in ß cells after birth (21, 70). Previously, we reported that transgenic mice expressing ATF3 under the control of the transthyretin promoter have defects in glucose homeostasis (2). However, the transthyretin promoter fragment directed the expression of ATF3 in both the liver and pancreatic ductal epithelium (2). Therefore, it was not possible to ascertain the impact of ATF3 expression in islets. Using the PDX-ATF3 construct, we obtained five transgenic founders which did not express the transgene (presumably due to mosaicism or silencing), but could pass it on to the progeny. F1 mice from all five founders expressed the transgene and died before mating. Therefore, no transgenic lines were established and all results were derived from the analyses of F1 mice. Three founders gave rise to litters of small size and low transgenic transmission rate (much lower than the expected 50%). The remaining two founders gave rise to the expected transgenic transmission rate (approximately 50%) and their progeny was further analyzed. F1 mice (PDX-ATF3) from founder 1 died within several days after birth and displayed islets with reduced size (Fig. 4b) and number (5 ± 0.05 versus 20 ± 0.1 per 107 pixel area in nontransgenic mice, P < 0.01). Analyses of islet population indicated a shift in size distribution toward small islets in the transgenic mice (Fig. 4c). Immunofluorescence analysis indicated abnormal distribution of hormone-positive cells (Fig. 4d). Transgenic pancreata (lower panel) had fewer insulin-positive cells (green) than nontransgenic pancreata (upper panel). Furthermore, glucagon-positive cells (red) in transgenic pancreata formed clusters with insulin-positive cells but failed to form the proper mantle/core arrangement of the /ß cells as in the nontransgenic pancreata (glucagon-positive cells at the periphery of the islets and insulin-positive ß cells at the core). These transgenic mice had low body weight, and defects consistent with ß-cell deficiency (transgenic versus nontransgenic, P < 0.001): high glucose, low insulin, high ß-hydroxybutyrate, and high triglyceride (Table 1). Due to the small size of the mice, sera from three to four mice were combined as one sample for analyses, and at least four samples were used to generate the above data. Analysis of glucagon did not show statistically significant difference between transgenic and nontransgenic mice (Table 1). F1 mice from founder 2 displayed less severe phenotypes. Although the precise reasons are not clear, variation in the severity of phenotypes among different transgenic founder lines is a common phenomenon. Islets from progeny of founder 2 were not greatly reduced in size or number, but displayed abnormal morphology with rough surface (not shown). Many of these mice died before 1 week and none survived to adulthood.
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/ß cells in rodent islets, human islets have composites of several rodent-like islet subunits (5; S. Bonner-Weir, personal communication). Taken together, these immunohistochemistry data (from NOD mice, type 1 and type 2 patients) support the notion that ATF3 is expressed in insulin+ cells. Recently, ATF3 was reported to be expressed in wild-type glucagon+ cells (66). We do not know the reasons for this apparent discrepancy, except that it may be due to the differences in strains or antibodies.
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DISCUSSION |
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Since ß-cell apoptosis plays an important role in the pathophysiological progression of diabetes, our results support the speculation that stress-induced expression of ATF3 plays a role in diabetes. However, much more work is required to substantiate this speculation. In an attempt to test the potential role of ATF3 in diabetes, we analyzed wild-type and ATF3 knockout mice using the multiple low-dose streptozotocin (MLD-STZ) model (38, 39), where insulitis and hyperglycemia are induced in male mice in an accelerated manner (over a 2-week period) following five daily injections of low does STZ (40 mg/kg of body weight). Importantly, previous studies have demonstrated an autoimmune component in this diabetes model (see reference 29 and references therein). Preliminary results from analysis of 20 mice in each group showed no significant difference in the blood glucose levels of ATF3 knockout mice from that of wild-type mice (data not shown). We suggest two potential explanations for this result. First, knockout of one stress-inducible gene, ATF3, is not sufficient to protect islets from the level of insults induced by STZ. As described above, ATF3 knockout does not provide significant protection from apoptosis when TNF- or Fas pathway was activated. Since apoptosis is regulated by complex cellular processes that involve many cross-interacting pathways and genes, it is reasonable that knockout of ATF3 alone is not sufficient for full protection. Second, ATF3 knockout mice may be partially protected from STZ-induced insults but the protection is not discernible by measuring the blood glucose levels. Thus, more work including detailed histological analysis is necessary for definitive conclusion. In this context, we note that knockout of IL-1 receptor was recently reported to delay, but not prevent, diabetes in NOD mice (61).
On the basis of our observations and reports on iNOS in the literature, we propose the following model. Expression of ATF3 and iNOS genes is induced by cytokines, at least in part, through the NF-B and JNK/SAPK signaling pathways. The induction of iNOS leads to NO production, which in turn further induces ATF3 gene expression. This supposition is supported by a recent observation that iNOS inhibitor reduced cytokine-induced ATF3 expression in INS-1 ß cells at late time points (>8 h) but not at the early time points (34). Since elimination of either ATF3 or iNOS reduced cytokine-induced apoptosis (see reference 41 for iNOS knockout and this report for ATF3 knockout), it appears that induction of both genes is necessary for efficient ß-cell death.
As shown in our results, ATF3 knockout islets were protected from 2 cytokine (IL-1ß-IFN-)-induced apoptosis, but not three-cytokine- or two-cytokine-plus-Fas-induced apoptosis. One element common to Fas and TNF- (the third cytokine) is the activation of the death receptor pathway—the FADD-caspase 8 pathway (4, 10, 64). Therefore, our results suggest that ATF3 plays a role for (IL-1ß-IFN-)-induced apoptosis but may not play a significant role in the death-receptor pathway. We note that NO was reported to mediate cell death in ß cells via a pathway distinct from Fas-mediated pathway (72).
Although ATF3 is induced by a variety of seemingly diverse stress signals such as ischemia-reperfusion, hyperglycemia, hyperlipidemia, cytokines, and UV light, many of these signals elicit oxidative stress, that is, an imbalance between the reactive species and antioxidant molecules (57). Therefore, ATF3 can be viewed as an oxidative-stress induced gene. Consistent with this notion, ATF3 is induced by H2O2 and this induction is repressed by the antioxidant N-acetyl-L-cysteine (2). Accumulating evidence indicates that oxidative stress induces a variety of responses relevant to diabetes, including activation of the NF-B and JNK/SAPK pathways, insulin-resistance, ß-cell dysfunction, and ß-cell destruction (17, 18, 43, 57). Therefore, our finding that ATF3, an oxidative-stress-inducible gene, plays an important role in ß-cell destruction (and perhaps diabetes) is consistent with the current literature. The significance of our finding is that it is the first to implicate ATF3 in ß-cell apoptosis, and it supports a potential link between ATF3 and iNOS in cytokine-induced gene networks (34).
Recently, gadd153/CHOP knockout islets were demonstrated to be partially protected from NO-induced cell death (51), a result similar to that from the ATF3 knockout islets. Previously, we demonstrated that gadd153/CHOP is an ATF3-interacting protein (9) and its corresponding gene may be a downstream target of ATF3 (69). Therefore, ATF3 may affect the ability of NO to modulate the cell death machinery either directly or indirectly—through the interaction with other proteins or the regulation of downstream genes (such as gadd153/Chop10). We note that both ATF3 and gadd153/CHOP are induced by endoplasmic reticulum (ER) stress (8, 31, 67). Significantly, deletion of gadd153/CHOP gene has been demonstrated to delay the onset of diabetes in Akita mice (50), a model where diabetes is thought to be induced by ER stress (65). Therefore, it would be interesting to see whether the deletion of ATF3 also protects ß cell from ER stress-induced apoptosis and delay the onset of diabetes in Akita mice. Finally, ATF3 is induced in ß cells by cytokines and elevated glucose or FFA and is expressed in the islets of type 1 and 2 patients, supporting the emerging notion that the mechanisms leading to ß-cell death in both forms of diabetes may share more similarity than previously thought.
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ACKNOWLEDGMENTS |
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This work was supported by grants NIH ES08690 and DK59605, ADA research grant 868688 (T.H.), grants NIH DK47119 and ES08681 (D.R.), the Juvenile Diabetes Research Foundation (M.P.), and grant JDRF 2000-719 (S.T.G.). M.P. is a Canadian Institute of Health Research (CIHR) Scientist, and J.B. is supported by a CIHR Ph.D. studentship.
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FOOTNOTES |
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Supplemental material for this article may be found at http://mcb.asm.org/.
Present address: College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Present address: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.
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