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Richard Watkin,1, Brian McElhinney,1, Amy Guala,1 Matthew L. Poynter,1 Rebecca L. Persinger,1 Ralph Budd,2, and Yvonne Janssen-Heininger1*
Departments of Pathology,1 Medicine, University of Vermont, Burlington, Vermont 054052
Received 16 April 2004/ Accepted 13 May 2004
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ABSTRACT |
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INTRODUCTION |
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Despite the great potential of causing damage, NO2 is a poorly studied oxidant and the mechanisms by which it evokes cell death remain enigmatic. Inhalation studies employing NO2 in rodents have demonstrated injury to the pulmonary epithelium (46, 47), without elucidating specific targets of NO2 attack. Previously, we have shown that lung epithelial cells exposed to NO2 or ONOO– undergo cell death that is density dependent and selectively occurs at the leading edge of a wounded cell culture (51). The c-Jun N-terminal kinase (JNK) member of the family of mitogen-activated protein kinases, also known as stress-activated protein kinase (SAPK), is regulated in a density-dependent manner (34) and is known to be activated by environmental stresses (12, 29), including oxidative stress (22, 32, 50, 66).
JNK has been implicated in multiple physiological processes, including survival (35) and apoptosis (12), and the consequences of its action appear to depend upon the cell type or stimulus under investigation, the extent and duration of its activity, as well as the engagement of other signaling modules. A causal relationship between JNK activation and apoptosis was first established in neuronal cells after neurotrophic factor withdrawal (68) and was confirmed in mice with a targeted disruption of the neuronal gene, jnk3 (69) or mice containing a mutation in the c-jun gene that lacked the JNK phosphorylation sites (3). This observation initially suggested that transcriptional events were important in JNK-dependent apoptosis, and one candidate gene product was Fas ligand (20, 33). However, gene knockout studies demonstrated that caspase 8, the initiator caspase required for Fas-dependent cell death, was not required for UV-induced cell death (62), suggesting that alternative pathways regulate stress-induced JNK-dependent cell death. It is now well established that mitochondria can play an important role in JNK-dependent stress-induced apoptosis (38, 60, 62), via JNK-induced phosphorylation of the BH3-only proteins Bim and Bmf, and the subsequent release from dynein and myosin V motor complexes, thereby engaging the mitochondrial apoptotic pathway (37).
Activation of death receptors is known to mediate JNK activation (7, 57, 58, 70), which in some cases contributes to the apoptotic process (57, 58), although many controversies exist (7, 10, 26, 39, 59, 64, 70). Fas and tumor necrosis factor receptor 1 (TNF-R1) receptors share characteristic cysteine-rich repeats in their extracellular domains, and cytoplasmic death domains that are critical for signaling to apoptosis (9, 65). Upon Fas stimulation, a death-inducing signaling complex (DISC) is formed by the recruitment of Fas-associated death domain protein (FADD) and caspase 8 or 10 to the intracellular death domain, which results in autoproteolytic processing of the caspases that trigger the apoptotic cascade (65). FADD also interacts with TNFR-1 via an adapter protein, TNF receptor-activated death domain (TRADD), and is required for the induction of caspase 8-dependent apoptosis (9).
The goal of the present study was to investigate whether the activation of JNK also plays a role in cell death caused by the RNS, NO2, or ONOO–. Since membrane-localized death receptors represent likely targets for interaction with RNS, which are highly membrane reactive (23), we investigated the involvement of Fas and TNF-R1 in the molecular responses to these highly reactive species.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD) were provided by Richard Siegel and Michael Lenardo (National Institutes of Health). FADD (80-205) was provided by Peter Vandenabeele (University of Ghent, Ghent, Belgium). As a positive control, cells were treated with FasL + M2 (recombinant Flag-tagged human FasL [Alexis Biochemicals; 100 ng/ml] plus anti-Flag antibody M2 [Sigma; 1 µg/ml]) in order to cross-link recombinant FasL. TNF-
was obtained from GIBCO, the generic caspase inhibitor zVAD-FMK was from Promega, Fas:Fc was from Alexis, anti-FasL antibody (MFL-4) was from Pharmingen, and a phospho-specific MKK4 antibody was purchased from Cell Signaling Technologies. Exposure to RNS. Exposure to NO2 was performed inside a modified, stainless steel cell culture cabinet as described in detail elsewhere (51). Briefly, NO2 was generated from a tank containing 1,000 ppm of NO2 in nitrogen (Messer MG Industries). An Ionics nitric oxide analyzer (NOA) equipped with an NO2 thermal converter or an Eco-Physics analyzer was used to measure NO2 in the gas phase according to the manufacturers' instructions. Cells were exposed to 10 ppm of NO2 for 4 h on orbital rotating platforms, allowing exposure to gas-phase NO2 in 50% of the culture dish at any given time. In order to maximize the stability of gas-phase exposures, which can be problematic over a time course of 4 h, selected experiments utilized 2-h exposure regimens of 40 ppm of NO2. Both exposure schemes caused marked cell death and JNK activation (data not shown). Air-exposed mock manipulations were performed by rocking cells on an orbital rotating platform under standard culture conditions. Pure ONOO– was obtained from Calbiochem. In control experiments, ONOO– was decomposed overnight at room temperature prior to exposure to cells (31). In general, each experiment contained two independent observations per treatment group, and experiments were repeated at least two times.
Transient and stable transfections. C10 cells were transiently transfected with 2 µg of plasmids, using Lipofectamine plus (Invitrogen) according to the manufacturer's instructions. Flag-JNK1-APF was subcloned into pcDNA3.0 (Invitrogen). Stable cell pools for either pcDNA3.0 only or pcDNA3.0-Flag-JNK1-APF were generated by selection with neomycin (G418; GIBCO-BRL).
In vitro kinase assays and Western blotting.
Cell lysates were prepared from RLE or C10 cells of lung fibroblasts, as previously described (32). JNK1 was immunoprecipitated from 200 µg of protein sample using 1 µg of rabbit polyclonal antibodies (Santa Cruz Biotechnology). In some experiments, recombinant JNK1 was immunoprecipitated by using antibody directed against HA (Roche). Immunoprecipitated JNK1 was reacted in kinase buffer containing [
-32P]ATP and the substrate GST-Jun at 30°C for 30 min. Samples were then electrophoresed on 15% polyacrylamide gels and dried, and substrate phosphorylation was visualized by autoradiography. For phospho-specific c-Jun Western blots, whole-cell extracts were prepared by lysing cells in a hypertonic lysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 1% Nonidet P-40, 5 mM EDTA, pH 8.8, 1 mM phenylmethyl sulfonyl fluoride, 1 mM sodium orthovanadate) and 20 µg of total protein from each sample was used for Western blotting with a phospho-specific c-Jun antibody (KM-1; Santa Cruz) and detection via standard conditions.
Assessment of Fas clustering and oxidative modification. Cells grown on glass coverslips were untreated or treated with ONOO– (500 µM, 10 min) or 100-ng/ml sFasL plus 1-µg/ml M2 for 15 min. Cells were subsequently fixed in 3% para-formaldehyde in phosphate-buffered saline (PBS) for 30 min, washed, and permeabilized with 0.1% Triton X-100 for 20 min. Nonspecific binding was blocked with a mixture of 0.5% normal goat and 0.5% normal rabbit sera for 1 h, and slides were then incubated overnight at 4°C with primary antibody to FADD (Santa-Cruz FADD S18) and Fas (Santa-Cruz Fas FL-335). After three washes with PBS, slides were incubated with secondary antibodies, Alexa-568 antigoat and Alexa-488 antirabbit (Molecular Probes). Slides were subsequently washed three times in PBS and once in double-distilled water prior to mounting. Colocalization was evaluated with a Bio-Rad MRC 1240 laser-scanning confocal microscope. Control experiments included single incubations as well as incubations with nonspecific primary and secondary antibodies alone and revealed minimal cross-reactivity or background fluorescence. In order to assess whether Fas is a direct target for oxidation by ONOO–, Fas was immunoprecipitated and tyrosine nitration was assessed by Western blotting using a nitrotyrosine-specific antibody (Upstate Biotechnology). To assess the extent of cysteine oxidation of Fas, cell lysates were prepared in the presence of 0.05 mM sulfhydryl-specific biotinylating agent, N-(3-malemidylpropionyl) biocytin (MPB; Molecular Probes) for 30 min at room temperature, resulting in biotinylation of reduced cysteines. Fas was immunoprecipitated, and the extent of biotinylation was determined by using streptavidin peroxidase.
Determination of cell death. After selected time points of exposure, cells were washed in PBS and incubated with the mitochondrial stain JC-1 (Molecular Probes) in order to visualize respiring mitochondria (red). Loss of mitochondrial respiration results in a lack of JC-1 aggregation, which causes a green staining pattern (11). The nuclear morphology was assessed with Hoechst (Sigma). The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay (Molecular Probes) was used to assess overall viability by monitoring the production of formazan at 540 nm.
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RESULTS |
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CD) were fully capable of activating JNK in response to treatment with ONOO–, whereas the ability of TNF- to activate JNK was blunted (Fig. 3C). Similarly, NO2-induced JNK activation was prevented in cells expressing extracellular domain of Fas but not TNF-R1 (Fig. 3D). In support of the observations in Fig. 3A to D, fibroblasts generated from LPR mice were completely refractory from ONOO–-induced JNK activation, whereas fibroblasts from mice lacking TNF-R1 were normally responsive to ONOO–-dependent activation of JNK (Fig. 3E). Lastly, LPR fibroblasts also were partially protected from ONOO–-induced cell death (Fig. 3F). Collectively, these data clearly demonstrate that Fas, but not TNF-R1 is an important target for JNK activation by RNS and, consequently, cell death.
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RNS-induced JNK activation requires CRD2 and CRD3, but not CRD1. FasL-Fas receptor interaction are believed to occur predominantly via the cysteine-rich domains (CRDs) in the extracellular regions of these receptors (56). In the absence of membrane-bound ligand, inactive complexes of Fas are formed via the self-association domain in CRD1, termed the preligand assembly domain (PLAD) (55), which is required for apoptosis signaling. To explore whether this domain is also required to engage ONOO– to cause JNK activation, we expressed a truncated version of Fas lacking both the PLAD and death domains (Fas 67-210; Fig. 7A), and evaluated JNK activation by ONOO–. As shown before (Fig. 3), cells expressing extracellular domain of Fas with a truncated death domain (positions 1 to 210) were completely resistant to JNK activation by ONOO– (Fig. 7C). Cells expressing Fas 67-210, were also largely refractory to JNK activation by ONOO–, illustrating that dominant interference with signaling still occurs in the absence of CRD1. In contrast, JNK activation by FasL + M2 was partially restored in cells expressing Fas 67-210, in line with the requirement of CRD1 in FasL-induced cell death (55). These data demonstrate the requirement of CRD2 and CRD3, rather than CRD1, for ONOO–-induced JNK activation and illustrate the lack of requirement of the PLAD for interaction with RNS.
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DISCUSSION |
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JNK has been shown to be important in cell death after exposure to oxidants, such as - or UV-C irradiation (5, 10) or H2O2 (45, 66). Here, we demonstrate that RNS are potent activators of JNK and that JNK is causally involved in cell death, measured by mitochondrial depolarization and nuclear condensation, which were almost completely prevented in cells expressing JNK1-APF and attenuated in cells lacking JNK1. Furthermore, we also demonstrate that RNS require Fas, but not TNF-R1, to activate JNK and that Fas is a direct target for RNS-induced oxidation and membrane relocalization. Surprisingly, RNS-induced Fas signaling to JNK occurred in a caspase- and FasL-independent manner, but required FADD. While engagement of TNF-R1 is well known to cause JNK activation via recruitment of TRADD and TRAF-2 (9, 28) and that JNK activation controls apoptosis via TNF-R1 (57, 58), the link between Fas ligation, JNK activation, and apoptosis remains a topic of considerable debate (7, 10, 26, 39, 59, 64, 70). Fas was reported to engage JNK via the Daxx-dependent activation of apoptosis signal-regulating kinase 1 (ASK1) (7, 70). However, this finding has been brought into question by other investigators (26, 59, 64). Furthermore, JNK activation by Fas ligation has been demonstrated to occur as a result of caspase-dependent activation of the JNK kinase kinase, mitogen-activated protein kinase/Erk kinase kinase 1 (MEKK1) (13), and consequently, caspase inhibitors attenuated FasL-induced JNK activation (26, 39, 64), suggesting that JNK activation following Fas ligation may be the consequence of activation of the apoptotic machinery, rather than the effector. Our results strongly suggest that Fas can directly signal to JNK in cells exposed to RNS, pointing to a unique FasL-independent mechanism of activation of Fas by RNS. These observations distinguish RNS from other stresses that cause JNK-dependent apoptosis, which required transcriptional activation of FasL (17, 19, 20, 40). Although we have not ruled out that transcriptional events do not contribute to RNS-induced JNK-dependent cell death, the relatively short time frame after which cell death becomes apparent (Fig. 2) (data not shown) and the JNK-dependent mitochondrial perturbations strongly suggest that a mitochondrial-dependent pathway (37, 38, 60, 62) rather than JNK-dependent activation of death effector genes is responsible for RNS-induced cell death.
The lack of caspase involvement in JNK activation or cell death by RNS is not surprising given the fact that RNS are strong cysteine oxidizers (1) (Fig. 6) and that caspases contain a critical cysteine in their catalytic domain, required for activation. Compelling data exist demonstrating that nitrosylation of caspases represses their activity (42) and that the oxidant hydrogen peroxide (H2O2) can interfere with the caspase activation process (36). Furthermore, the activation of caspase 8 in the DISC is dependent on glutathione (25), which is depleted by RNS (44). A mixed mode of cell death with features of necrosis has also been reported in cells exposed to hyperoxia, although this was protracted and associated with recruitment of caspase 8 to Fas (67). Studies demonstrating that Fas ligation can lead to necrotic cell death when caspases are inhibited, the requirement of FADD herein, the loss of mitochondrial membrane potential, and the production of reactive oxygen species (14, 21, 43, 63) are in line with our present observations. Although we demonstrated a requirement of FADD in the Fas-dependent JNK activation by RNS, the subsequent biochemical events leading to JNK activation remain elusive, but may involve MKK4 (Fig. 3B). It is tempting to speculate that the kinase activity of the serine/threonine kinase, receptor-interacting protein (RIP), which binds to the death domain of Fas and is required for necrotic signaling by Fas (24, 27), also could be required for signaling by RNS. The molecular mechanisms that connect FADD and RIP to the execution of necrotic cell death and the involvement of JNK herein remain to be elucidated. Nonetheless, our present observations demonstrating that JNK activation by RNS was inhibited by a FADD mutant lacking the death effector domain and was caspase independent strongly suggest a similar mode of non-caspase-dependent cell death through Fas, although additional experiments will be required to test this possibility formally.
Our observations demonstrating that RNS require Fas, but not TNF-R1, to signal to JNK are intriguing, given the high degree of homology between these proteins. We recently demonstrated that the oxidant H2O2 utilizes TNF-R1 to signal to JNK (49). Similarly, JNK activation by H2O2 was also attenuated in cells expressing Fas 1-210 (data not shown), illustrating that JNK activation by H2O2 requires Fas and TNF-R1, whereas RNS preferentially target Fas. This difference may stem from the unique reactivity of RNS, compared to H2O2, and/or the location of the oxidative attack. We demonstrate here that Fas is indeed directly oxidized by RNS, illustrating that this receptor is a direct target. The extracellular domains of death receptors, including Fas and TNF-R1, contain multiple CRDs. Fas contains three CRDs, whereas TNFR-1 has four CRDs. The amino acid residues in CRD2 and CRD3 of Fas are conserved in murine and human Fas, but not in TNF-R1 (56). Furthermore, CRD1 but not CRD2 or CRD3 of Fas can be exchanged for the homologous domain found in TNFR-1 for Fas ligand binding (48). These observations, coupled with our findings that Fas but not TNFR-1 is required for RNS-induced activation of JNK and that CRD2 and CRD3 of the extracellular domain of Fas receptor are the required domain to sustain JNK activation by RNS, may explain the specificity of RNS for its interaction with Fas rather than TNFR-1. Finally, our observation demonstrating that CRD1 of Fas, which is required for formation of preassembled Fas complexes, interaction with FasL, and downstream signaling (55), is not required for JNK activation by RNS suggests that RNS interacts with Fas in a manner distinct from FasL. It is plausible that cysteine or other oxidation events in CRD2 and/or CRD3 are responsible for RNS-induced aggregation of Fas (Fig. 6), although the exact sites and modes of oxidation are unknown at this time. Tyrosine nitration of Fas was recently described in rat livers following administration of lipopolysaccharide, illustrating that RNS directly target Fas under inflammatory conditions in vivo. However, the same report demonstrated that although ONOO– directly targeted Fas, it prevented FasL-induced DISC formation and subsequent apoptosis independently of JNK (53). The discrepancy between these findings and our work is puzzling and may be related to the requirement of epidermal growth factor receptor association with Fas in hepatocytes and its subsequent tyrosine phosphorylation, which was prevented by ONOO– (53). While that study demonstrated that ONOO– also caused apoptosis in hepatocytes, the contribution of Fas therein was not conclusively elucidated. Nonetheless, their findings and the findings from our study demonstrate that Fas is an important target of RNS.
In summary, we have demonstrated here that RNS directly attack Fas and consequently trigger JNK-dependent cell death. Further investigation into the precise location of oxidative attack by RNS and confirmation that this occurs in intact tissues will be important in designing strategies to limit death signaling by RNS, which might be beneficial in combating the tissue-damaging effects of RNS that accompany chronic inflammatory diseases.
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ACKNOWLEDGMENTS |
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This work was supported by the Public Health Service: P20 RL15557 (NCRR COBRE), NIH RO1 HL60014, and PO1 HL67004.
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FOOTNOTES |
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C.P., R.W., and B.M. contributed equally to this work.
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