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Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute,1 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,3 Department of Community, Occupational and Family Medicine, Faculty of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore,2 Department of Pharmacology, University of California, San Diego, San Diego, California,4 Department of Microbiology & Immunology, Thomas Jefferson University Medical College, Philadelphia, Pennsylvania5
Received 4 September 2003/ Returned for modification 27 October 2003/ Accepted 29 March 2004
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ABSTRACT |
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INTRODUCTION |
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B and activator protein 1, and some cell stress-activated kinases (6, 23, 43, 49). Apparently, the cell signaling pathways regulating ROS-induced cell death remain to be further investigated.
In recent years, extensive research on the TNF signaling pathway has greatly advanced our understanding of the cell death mechanisms. It is well known that receptor-interacting protein (RIP), TNF receptor (TNFR)-associated factor 2 (TRAF2), and Fas-associated death domain protein (FADD) are important effector molecules of TNFR1 signaling (4, 8, 38). In response to TNF, TNFR1 is trimerized and recruits TNFR-associated death domain protein (TRADD) as an adaptor molecule. The recruited TRADD interacts with FADD, which then interacts and activates caspase 8 to initiate the apoptotic cell death pathway. On the other hand, TRADD interacts with RIP and TRAF2 that is known to be important in TNF-induced activation of nuclear transcription factor NF-B and mitogen-activated protein kinases (MAPK) (14).
Although it is well established that RIP and TRAF2 mainly act as cell survival factors to protect against TNF-induced apoptosis via NF-B activation (4, 31, 37), little is known about their involvement in cell death elicited by other stimuli. An earlier study revealed that RIP is required for Fas-induced caspase-independent cell death in primary T cells (26), indicating diversified functions of RIP in the regulation of the cell death process. On the other hand, ROS and oxidative stress are known to be involved in TNF-induced cell death (12, 16, 46). However, currently there is no report concerning whether some of the key TNF signaling molecules such as RIP and TRAF2 serve as the molecular targets of ROS in cell death. In this study, we demonstrate that RIP, TRAF2, and FADD, three key TNF signaling molecules, are important regulators in H2O2-induced cell death. We found that mouse embryonic fibroblasts (MEF) deficient of RIP and TRAF2 are largely resistant, while FADD–/– MEF cells are highly sensitive to H2O2 cytotoxicity, when compared to wild-type (wt) cells. Reconstitution of these proteins significantly restores the responses of these knockout cells to H2O2. Moreover, RIP and TRAF2 form a complex upon H2O2 exposure, most probably through membrane lipid rafts but independently of TNFR1. Lastly, we demonstrate that activation of c-Jun NH2-terminal kinase 1 (JNK1) is the key downstream event responsible for H2O2-induced cell death. Thus, our study reveals a novel cell signaling mechanism that regulates oxidative stress-induced cell death.
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MATERIALS AND METHODS |
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was purchased from R&D. Both wt RIP and RIP kinase dead RIPK45A constructs were reported previously (37). Cell culture and transient transfection. The wt and various knockout MEF cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, glutamine (2 mM), penicillin (100 U/ml), and streptomycin (100 µg/ml). The stable cell lines of the reconstituted cells were also cultured in the above complete medium with the presence of hygromycin (150 ng/ml). The wt Jurkat and RIP-deficient Jurkat cells were cultured in RPMI 1640 medium with the addition of 10% fetal bovine serum, glutamine (2 mM), penicillin (100 U/ml), and streptomycin (100 µg/ml). The transient transfection was performed using Lipofectamine Plus reagent (Invitrogen) by following the manufacturer's instructions.
Detection of cell death. Upon various designated treatments, cell death in MEF was quantified using a cytotoxicity detection kit (Roche) measuring the percentage of lactate dehydrogenase (LDH) leakage. In the transient transfection experiments, following H2O2 exposure, cells were fixed in 4% paraformaldehyde and stained with X-Gal (5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside). H2O2-induced cell death was then quantified by calculating the percentage of the remaining blue-stained cells in each group in comparison to their respective controls (37).
Western blotting and coimmunoprecipitation assay. For Western blotting, cells were first treated as described in the figure legends, and they were then collected and washed with phosphate-buffered saline (PBS) twice before they were lysed in M2 buffer (20 mM Tris at pH 7, 0.5% NP-40, 250 mM NaCl, 3 mM EDTA, 3 mM EGTA, 2 mM dithiothreitol, 0.5 mM phenylmethylsulfonyl fluoride, 20 mM glycerol phosphate, 1 mM sodium vanadate, 1 µg of leupeptin/ml). The cell lysate was collected after centrifugation (12,879 x g, 5 min), and about 30 µg of protein was then fractionated on gradient sodium dodecyl (SDS)-4 to 20% polyacrylamide gel electrophoresis (PAGE) (Bio-Rad) and blotted onto polyvinylidene difluoride membrane (Millipore). After blocking in 5% milk in PBST (PBS with 0.05% Tween 20), the membrane was probed with various antibodies and developed with enhanced chemiluminescence by following the manufacturer's instructions (Amersham).
For the coimmunoprecipitation experiments, cell lysate was prepared as described above. The cell lysate was mixed and incubated with various antibodies and protein A-Sepharose beads (Roche) by incubation at 4°C overnight. After extensive washing with the lysis buffer, beads were boiled in SDS sample buffer, and the bound proteins were resolved on 4 to 20% gradient SDS-PAGE (Bio-Rad). Detection was accomplished by Western blot analysis.
JNK kinase assay.
After various treatments, cells were collected and lysed in M2 buffer. JNK1 was immunoprecipitated with anti-JNK1 antibody (BD Pharmingen) and harvested with protein A-Sepharose beads (Roche). After extensive washing, the kinase assay was performed in complete kinase assay buffer (20 mM HEPES [pH 7.5], 20 mM ß-glycerol phosphate, 10 mM MgCl2, 1 mM dithiothreitol, 10 mM p-nithrophenyl phosphate, 50 µM sodium vanadate, 20 µM ATP) with the addition of p32-
-ATP and glutathione S-transferase-c-Jun as substrate. After incubation at 30°C for 30 min, the reaction was stopped with the addition of SDS sample buffer. The samples were then separated on a 4 to 20% gradient SDS-PAGE and visualized by autoradiography.
Immunofluorescence staining and confocal microscopy. The labeling of membrane lipid rafts with CTxB was conducted as previously reported (52). Cells were first stained with FITC-conjugated CTxB (10 µg/ml in PBS, 4°C for 30 min; Sigma), followed by H2O2 treatment (500 µM in DMEM, 37°C) for up to 30 min. Cells were then fixed in freshly prepared 3% paraformaldehyde, followed by permeabilization and blocking in 0.4% Triton X-100 with 20% goat serum. Immunofluorescence staining of RIP was performed using anti-RIP mouse monoclonal antibody (1:200; Transduction Laboratory) and a goat anti-mouse secondary antibody (1:1,000) (Alexa Fluor 594; Molecular Probes). All fluorescence images were obtained using a Zeiss confocal microscope (LSM 510 META).
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RESULTS |
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Despite the well known functions of RIP and TRAF2 in TNF signaling (4, 8, 38), it is not clear whether these cell signaling molecules are involved in other cell death signaling pathways. An early study suggested that RIP is involved in Fas- or TNF-induced caspase-independent cell death (26). Here, we examined whether RIP or TRAF2 is required for ROS-induced caspase-independent cell death. To do so, we compared H2O2-induced cell death in both wt and various knockout MEF cells in which the RIP, TRAF2, or FADD gene was disrupted (33, 61, 63) (Fig. 1A). When cells were treated with H2O2 (500 µM, 12 h) to undergo cell death, RIP–/– and TRAF2–/– cells were found to be H2O2 resistant when compared to wt MEF (Fig. 1B and C). In contrast, FADD–/– cells were more sensitive to H2O2-induced cell death than wt cells. Interestingly, such responses were found to be the opposite of TNF-induced apoptotic cell death (Fig. 1D): both RIP–/– and TRAF2–/– cells were hypersensitive to TNF-induced apoptosis, while FADD–/– cells were completely resistant. Therefore, RIP, TRAF2, and FADD play disparate roles in H2O2-induced cell death versus TNF-induced apoptosis, which depends on the activation of a caspase cascade initiated by caspase-8 activation (3, 4).
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H2O2-induced cell death is independent of TNFR1 and de novo protein synthesis.
Two important nuclear transcription factors, NF-B and activator protein 1, have been implicated in oxidative stress-induced cell death and proliferation (32). In this study, NF-B was not activated by H2O2 treatment in wt MEF cells, based on the luciferase reporter assay (data not shown). Moreover, H2O2-induced cell death does not require de novo protein synthesis, as pretreatment with the protein synthesis inhibitor, CHX, failed to affect H2O2-induced cell death (Fig. 4A). The effectiveness of CHX treatment was confirmed by the time-dependent decrease of the c-Myc protein level. This result thus indicates that H2O2-induced cell death is not mediated through an autocrine pathway.
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RIP and TRAF2 form a complex in response to H2O2 exposure. In order to understand the mechanism of RIP- and TRAF2-mediated ROS-induced cell death, we then investigated whether H2O2 can induce complex formation between RIP and TRAF2, as previously shown for TNF signaling (13, 28). While immunoprecipitation of TNFR1 failed to bring down any RIP and TRAF2 following H2O2 treatment (data not shown), a rapid and transient interaction between RIP and TRAF2 was found upon H2O2 exposure by immunoprecipitating TRAF2 (Fig. 5A). This interaction was detected as early as 5 min after H2O2 treatment and peaked at about 30 min. In contrast, TRADD, another important molecule in the TNF signaling pathway (29), was not detected in the complex (Fig. 5A). The TRAF2-RIP interaction is believed to be specific because other proteins, such as GRP78/BiP (20), were not part of the complex (Fig. 5A). The above finding was further confirmed by the reverse coimmunoprecipitation experiment using anti-RIP (Fig. 5B). Therefore, RIP and TRAF2 may mediate H2O2-induced cell death through forming a signal complex without TNFR1.
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JNK1 mediates H2O2-induced cell death downstream of RIP and TRAF2.
The next important question was how RIP and TRAF2 mediate H2O2-induced cell death. JNK and p38 are members of the MAPK family that play pivotal roles in cellular responses to stress (30, 34). Although the functions of JNK and p38 in apoptosis have been extensively studied, their roles in oxidative stress-induced cell death have not been clearly defined (32, 39). Here, we first tested the involvement of p38 in H2O2-induced cell death by using MEF cells lacking p38 isozymes. MEF derived from p38–/– mice, which are completely devoid of p38 activity (54), were as sensitive as wt MEF cells to H2O2-induced cell death (Fig. 6A). In contrast, MEF derived from JNK1–/– mice were resistant to H2O2, indicating that JNK1, but not p38, is required for H2O2-induced cell death.
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ROS are known to be potent activators of JNK, and JNK activation is also subject to redox regulation (55, 58). In this study, JNK activation by H2O2 could be detected as early as 5 min after treatment, with maximum levels reached by 30 to 60 min (Fig. 6B). The kinetics were found to be similar to those of H2O2-induced RIP and TRAF2 interaction as described earlier (Fig. 5A). More importantly, JNK1 activation by H2O2 was impaired in RIP–/– and TRAF2–/– cells (Fig. 6C). Thus, RIP and TRAF2 are needed for H2O2-induced JNK1 activation. In contrast, FADD is not involved in H2O2-mediated JNK1 activation, as FADD–/– cells exhibited levels of JNK activity after H2O2 treatment that were the same as for wt cells. Consistent with the insignificant role of TNFR1 in H2O2-induced cell death (Fig. 4C), H2O2-induced JNK activation is not impaired in TNFR1–/– cells (Fig. 6D), suggesting that H2O2 activates JNK independent of TNFR1. To shed light on the mechanism of H2O2-induced JNK1 activation, we examined whether RIP and TRAF2 mediate H2O2-induced JNK1 activation through the MAPK cascade (11). First, we tested if JNK1, MKK4/JNKK1, MKK7/JNKK2, MEKK1, or JNK-interacting protein (JIP) is present in the RIP and TRAF2 complex in response to H2O2. Surprisingly, only JNK1 was detected in the RIP-TRAF2 complex following H2O2 treatment (Fig. 6E and data not shown). This observation raised the possibility that RIP and TRAF2 mediate H2O2-induced JNK1 activation independently of the MAPK cascade. This possibility was further supported by the fact that dominant negative mutants of MKK4/JNKK1 and MKK7/JNKK2 had no effect on H2O2-induced JNK activation and cell death (data not shown).
To further support the important role of JNK activation in H2O2-induced cell death, we utilized SP600125, a specific JNK inhibitor (24). As shown in Fig. 7, SP600125 prevented H2O2-induced JNK activation and efficiently blocked H2O2-induced cell death. Taken together, our data suggest that JNK1 activation, downstream of RIP and TRAF2, is essential for H2O2-induced cell death.
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DISCUSSION |
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The involvement of RIP, TRAF2, and FADD in the TNFR1 signaling pathway has been well defined. Recruitment of FADD leads to the caspase cascade and apoptosis, while recruitments of the death domain kinase RIP and the adaptor protein TRAF2 mediate NF-B and MAPK activation (4, 8, 38). However, data from this study suggest that these key TNF signaling molecules also play a role in H2O2-induced cell death: RIP and TRAF2 mediate H2O2-induced cell death through activating JNK1, while FADD has an inhibitory effect in this process. JNK is one of the major cell stress-responsive kinases (11). Although the involvement of JNK in TNF-induced apoptosis is still inconclusive, it has been suggested that activation of JNK is required for ROS-induced cell death (10, 11, 56). Consistent with previous studies, data from this study further supported the critical role of JNK in ROS-induced cell death. More importantly, our data identified JNK1 as the main isoform of the JNK family that is involved in ROS-induced cell death. Currently, a number of important points remain to be further addressed. First, how does RIP and TRAF2 interaction mediate JNK1 activation? TRAF2 is known to interact directly or indirectly with several MAPK kinase kinases, such as apoptosis signal regulation kinase 1, TAK1, and MEKK1 (5, 40, 41). However, we failed to detect any of these components in the RIP and TRAF2 complex (data not shown), suggesting an alternate signaling pathway in H2O2-treated cells. Our observation that JNK1, but not MKK4/JNKK1, MKK7/JNKK2, or JIP, is present in the RIP and TRAF2 complex in response to H2O2 further supported this possibility. It is quite likely that RIP/TRAF2-mediated H2O2-induced JNK1 activation is achieved, independently of the MAPK cascade, through a similar mechanism of TAB1-mediated p38 activation. Moreover, although RIP and TRAF2 interaction seems to be transient following H2O2 treatment, such a transient interaction of RIP and TRAF2 could be accountable for the prolonged JNK activation due to the absence of the activation of NF-B in MEF (data not shown). Several recent reports have suggested that inhibition of NF-B activation results in the prolonged JNK activation in response to TNF treatment, although the recruitment of RIP and TRAF2 to the TNFR1 complex is transient. Another critical issue remaining to be further investigated is the downstream events after JNK1 activation in H2O2-induced cell death. The proapoptotic function of JNK has been extensively studied (11); however, little is known about how JNK mediates the cell death process. A recent study suggested that poly(ADP-ribose) polymerase activation mediated caspase-independent cell death elicited by DNA-damaging agent and H2O2 through the function of apoptosis-inducing factor (62). It remains to be further determined whether JNK activation is involved in this process.
One of the interesting findings from this study is that H2O2-induced cell death is TNFR1 independent based on the following observation: (i) TNFR1–/– cells showed the same susceptibility as wt cells to H2O2-induced cell death (Fig. 4B), (ii) TNFR1 protein is not detected in the RIP-TRAF2 complex upon H2O2 exposure (Fig. 5A), and (iii) H2O2 activates JNK1 in TNFR1–/– cells as potently as in wt cells (Fig. 6D). TNFR1 is one of the death receptors that include proteins such as Fas and DR3 (4, 38). Since it has been reported that Fas mediated UV-induced cell death independently of FasL (1), we tested the involvement of Fas in H2O2-induced cell death. We found that the Fas-deficient mouse T-cell hybridoma VD-1 cells (60) did not differ significantly from wt 2B4 cells in the response to H2O2-induced cell death (data not shown). We also tested the possibility of the involvement of DR3 in this process by examining the presence of DR3 in the RIP-TRAF2 complex. No DR3 was associated with RIP or TRAF2 in response to H2O2 treatment (data not shown). Therefore, it is unlikely that either Fas or DR3 plays a major role in ROS-induced cell death. Nevertheless, the discovery that H2O2 rapidly induces the formation of membrane lipid rafts with RIP colocalization (Fig. 5C) implied that the cell death signal in response to H2O2 is initiated in the cell membrane, most likely, through a receptor. Since we found that JNK1 is associated with the RIP-TRAF2 complex following H2O2 treatment, we also examined the localization of JNK1 and we found that JNK1 also colocalized with lipid rafts in response to H2O2 (data not shown).
Under physiological or pathological conditions, high levels of ROS are produced either intracellularly from mitochondria or exogenously from some adjacent phagocytes in the case of acute inflammation (15, 44). Based on the fact that H2O2 is highly cell permeable and capable of diffusing through the cell membrane freely (59), it is possible that exogenously produced or applied ROS act in a similar pattern as those generated intracellularly. Mitochondria-derived ROS have been implicated in TNF-induced necrotic cell death discovered in certain cell types, such as mouse fibrosarcoma L929 cells (16). One of the mechanisms is found to be the persistent activation of MAPK by ROS, a process suppressed by NF-B (46). Nevertheless, it remains to be seen whether those endogenously produced ROS in TNF-treated cells also require some of the upstream TNF signaling molecules such as RIP to convey the cell death signals.
Taken together, based on our study, it appears that RIP and TRAF2 have critical functions in a much broader spectrum of signal transduction pathways than was originally thought and act as the convergence point to relay different stimuli or stressors to different downstream signaling pathways that determine life and death for the cell.
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ACKNOWLEDGMENTS |
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H.-M.S. is on study leave from NUS and is supported in part by an Oncology Research Faculty Development Program from NIH.
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FOOTNOTES |
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