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The Journal of Immunology, 1998, 161: 776-781.
Copyright © 1998 by The American Association of Immunologists

HIV-Tat Protein Activates c-Jun N-Terminal Kinase and Activator Protein-11

Ashok Kumar*, Sunil K. Manna*, Subhash Dhawan{dagger} and Bharat B. Aggarwal2,*

* Cytokine Research Section, Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and {dagger} Laboratory of Immunochemistry, Division of Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Human immunodeficiency virus-1 tat (HIV-tat) protein, like other proinflammatory cytokines (such as TNF), activates a wide variety of cellular responses, some of which play a critical role in progression of HIV infection. Whether HIV-tat, like TNF, also activates c-Jun N-terminal kinase (JNK) and the transcription factor activator protein (AP)-1 is not known. We show that treatment of human histiocytic lymphoma U937 cells with the HIV-tat protein causes activation of JNK and AP-1 in a time- and dose-dependent manner. Transfection of a T cell line, H9 cells with the HIV-tat gene also resulted in an activation of JNK that was not further increased by treatment of cells with exogenous HIV-tat protein. Neutralizing Ab against HIV-tat inhibited the HIV-tat-mediated JNK activation. The activation of JNK by HIV-tat appears to be mediated through generation of free radical species, since pretreatment of cells with N-acetylcysteine (NAC) abolished the effect. Overall our results demonstrate that HIV-tat activates JNK and AP-1, which may contribute to the pathogenesis of AIDS.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Human immunodeficiency virus-1 tat (HIV-tat) is a virally encoded trans-activating protein of 76 amino acids that plays a critical role in replication of the HIV-1 virus (1, 2, 3). In addition to its trans-activation function, which is necessary for viral replication, HIV-tat can exert several effects on uninfected cells. It has been reported to modulate the proliferation of T cells and endothelial cells, probably by inducing the secretion of such growth regulatory cytokines as lymphotoxin (LT), TNF, IL-2, IL-4, and TGF-ß and by the expression of adhesion molecules and MHC class I molecules (4, 5, 6, 7, 8, 9, 10, 11, 12). The molecular mechanisms by which HIV-tat signals for this wide array of biologic functions remain unknown. Some of these effects, however, could follow by alteration in the activation of protein kinases and specific transcription factors.

Among these are the mitogen-activated protein (MAP)3 kinases, which are involved in a variety of cellular responses mediated by cytokines, hormones, and stress-inducing reagents (13). Depending upon the set of substrates they phosphorylate, MAP kinases are classified into at least three groups, including extracellular response kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 MAP kinase (14). The activity of activator protein-1 (AP-1), a transcription factor, which consists of a homodimer and heterodimers of members of the Jun family (c-Jun, JunB, and JunD) and heterodimers of the Jun and Fos (c-Fos, FosB, Fra1, and Fra2) families, is regulated, at least in part, by the activation of JNK (15, 16). JNK also plays an important role in the regulation of cellular proliferation (15). HIV-tat has been reported to activate NF-{kappa}B, a transcription factor involved in many inflammatory responses (17, 18). It has also been suggested that the activation of NF-{kappa}B is regulated by some upstream MAP kinases that also regulate JNK activation in the cells (19). Several cellular responses of HIV-tat mimic those of TNF. Finally, while TNF is known to activate JNK and AP-1, whether HIV-tat also activates is not known. In the present investigation we show that HIV-tat activates JNK and AP-1, possibly through generation of free radicals.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Materials

HIV-tat protein, neutralizing polyclonal Abs against HIV-tat, H9, Raji and Jurkat cells, and their HIV-tat gene-transfected counterparts were obtained from AIDS Research and Reference Reagent Program of the National Institute of Allergy and Infectious Diseases (Rockvile, MD). GST-Jun (1–79) was a kind gift from Dr. B. Su of the M. D. Anderson Cancer Center (Houston, TX). Anti-JNK1 Abs were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). The phospho-specific anti-p44/42 MAP Kinase (Thr202/Tyr204) Ab was obtained from New England Biolabs (Beverly, MA).

c-Jun N-terminal kinase assay

The assay for c-jun kinase was modified from a published protocol (20). After treatment of cells (3 x 106/ml) with HIV-tat or TNF, cell extracts were prepared by lysing cells in buffer containing 20 mM HEPES, pH 7.4, 2 mM EDTA, 250 mM NaCl, 0.1% Nonidet P-40, 2 µg/ml leupeptin, 2 µg/ml aprotinin, 1 mM PMSF, 0.5 µg/ml benzamidine, and 1 mM DTT. Cytoplasmic extracts (250 µg) were subjected to immunoprecipitation with 0.3 µg anti-JNK (Santa Cruz) for 30 min at 4°C. Immune complexes were collected by incubation with protein A/G-Sepharose beads (Pierce, Rockford, IL) for 30 min at 4°C. The beads were collected by centrifugation and washed extensively with lysis buffer (4 x 400 µl) and kinase buffer (2 x 400 µl:20 mM HEPES, pH 7.4, 1 mM DTT, 25 mM NaCl). Kinase assays were performed for 15 min at 37°C with 2 µg GST-Jun(1–79) in 20 µl containing 20 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM DTT, and 10 µCi [{gamma}-32P]ATP. Reactions were stopped with 15 µl SDS-sample buffer, boiled for 5 min, and subjected to SDS-PAGE. GST-Jun(1–79) was visualized by staining with Coomassie blue, and the dried gel was analyzed by a Phosphorimager (Molecular Dynamics, Sunnyvale, CA) and quantitated by ImageQuant Software (Molecular Dynamics).

MAP kinase kinase assay

U937 cells were treated with TNF or with different concentrations of HIV-tat protein for 30 min at 37°C. The cells were washed with PBS and extracted with lysis buffer containing 20 mM HEPES, pH 7.4, 2 mM EDTA, 250 mM NaCl, 0.1% Nonidet P-40, 2 µg/ml leupeptin, 2 µg/ml aprotinin, 1 mM PMSF, 0.5 µg/ml benzamidine, 1 mM DTT, and 1 mM sodium orthovanadate. Protein (50 µg) was resolved on 10% SDS-PAGE, electrotransferred onto nitrocellulose membrane, and probed with the phospho-specific anti-p44/42 MAP Kinase (Thr202/Tyr204) Ab (New England Biolabs) raised in rabbit (1:3000 dilution). The membrane was then incubated with peroxidase conjugated anti-rabbit IgG (1:3000 dilution), and bands were detected by chemiluminescence (ECL, Amersham, Arlington, Heights, IL).

Electrophoresis mobility shift assay

The electrophoresis mobility shift assay (EMSA) was performed by incubating 4 to 5 µg of nuclear extract with 16 fmol of 32P-end-labeled AP-1 consensus oligonucleotide 5'-CGCTTGATGACTCAGCCGGAA-3' (Santa Cruz) for 15 min at 37°C, as described earlier (21). The specificity of binding was examined by competition with unlabeled oligonucleotide. Visualization and quantitation of radioactive bands was conducted by phosphorimager (Molecular Dynamics) using Imagequant software.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To study the effect of HIV-tat protein on JNK activity, U937 cells were treated with different concentrations of HIV-tat for 10 min, and the cell lysate was immunoprecipitated with Abs against p46 isoforms of JNK. The activity of immunoprecipitated JNK was assessed using GST-c-Jun as a substrate. As shown in Figure 1GoA, treatment of U937 cells with HIV-tat activated JNK in a dose-dependent manner, with maximum effect occurring at a concentration of 100 ng/ml. Pretreatment of HIV-tat protein either with neutralizing Abs to HIV-tat (Fig. 1GoB) or with proteolytic enzyme trypsin or boiling at 100°C for 15 min abolished the ability of HIV-tat to activate JNK, thus suggesting the specificity of this effect (Fig. 1GoC).



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  		FIGURE 1. HIV-tat-mediated activation of JNK. A, U937 cells (3 x 106) were treated with different concentrations (1, 10, 100, and 1000 ng/ml) of HIV-tat protein for 10 min at 37°C. B, U937 cells were treated for 10 min at 37°C either with HIV-tat or with HIV-tat protein pretreated with different dilutions of anti-HIV-tat Ab or with control IgG Ab for 30 min at room temperature. C, U937 cells were treated for 10 min at 37°C with either untreated or trypsin-treated (2% w/v, for 3 h) or heat-denatured (exposed to 100°C for 15 min) HIV-tat protein. After all these treatments, the cells were lysed and the JNK activity was determined as described in the Materials and Methods. The results are from one representative of three independent experiments.

 
Recent reports indicate that time and duration of JNK activation may depend mainly on the type of activating signal (22, 23). Environmental stimuli, like UV radiation, {gamma}-irradiation, and the cancer chemopreventive agent phenethyl isothiocyanate (23, 24), cause a persistent activation of JNK, whereas other agents, such as TNF, produce a rapid transient activation (22). In the next part of this study, a time kinetics of HIV-tat-induced activation of JNK was studied. Cells were treated for different time intervals with 100 ng/ml of HIV-tat protein. As shown in Figure 2GoA, treatment of U937 cells with HIV-tat resulted in a rapid activation of JNK, which peaked at 10 min and 60 min time of treatment. Although the JNK activity was lower at 15 and 30 min, it was significantly higher than the basal level of JNK activity. Similar biphasic response was noted in three other independent experiments (data not shown). In contrast, treatment of U937 cells with TNF resulted in a rapid increase in JNK activity, which peaked at 10 min and returned to the basal level after 20 min (Fig. 2GoB). The reason for this biphasic activation of JNK by HIV-tat is not clear. The possibility that HIV-tat-induced JNK activation at two different time intervals is required for two different cellular responses cannot be ruled out. Indeed, some other growth regulatory molecules are known to cause a biphasic activation of gene expression (25).



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  		FIGURE 2. Effect of time of treatment of HIV-tat on the JNK activation. U937 (3 x 106) cells were treated with HIV-tat (100 ng/ml, A) or TNF (1 nM, B) for indicated times, and then the activation of JNK was examined as described. C, U937 cells were treated with either HIV-tat (50 or 100 ng/ml) or TNF (1 nM) for 30 min at 37°C, and the activation of MEK was studied as described in Materials and Methods.

 
To determine the specificity of the activation of JNK by HIV-tat, we also investigated the effect of HIV-tat protein on the activation of MAP kinase kinase (also called MEK), a kinase involved in TNF signaling and other growth factors. U937 cells were treated either with TNF (a known activator) or with 50 or 100 ng/ml of HIV-tat protein for 30 min at 37°C, and the MEK activation was examined. As shown in Figure 2GoC, treatment of U937 cells with TNF resulted in an activation of MEK. However, HIV-tat did not effect the activation of MEK. These results thus suggest that HIV-tat and TNF act through different mechanisms and that HIV-tat does not activate all the kinases involved in the TNF-mediated signal transduction.

In contrast to exogenous treatment, whether endogenously produced HIV-tat can activate JNK was also examined. We checked the activation of JNK in cells transfected with the HIV-tat gene. As shown in Figure 3GoA, the transfection of H9 cells with HIV-tat gene resulted in an increase in JNK activity. On treatment with exogenous HIV-tat protein, no further increase in JNK activity was observed in H9 cells transfected with the HIV-tat gene. The JNK activity of normal H9 cells was augmented on treatment with exogenous HIV-tat protein. H9 cells transfected with HIV-tat gene have been previously shown by Western blot analysis to produce HIV-tat protein in the culture supernatant (26), similar to HIV-infected cells.



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  		FIGURE 3. Activation of JNK in control and HIV-tat-transfected cells. A, Control and HIV-tat gene-transfected cells were treated with either medium or with 100 ng/ml of exogenous HIV-tat for 10 min. B, HIV-tat-transfected H9 cells were preincubated either with indicated dilutions of anti-HIV-tat Abs or with preimmune serum for 2 h at 37°C, and then JNK activity was examined as described in Materials and Methods. C, The levels of constitutive JNK activation in Jurkat and Raji cells transfected with HIV-tat gene was examined. The data are from one representative experiment of two independent ones conducted.

 
To determine that the constitutive JNK activation in HIV-tat gene-transfected H9 cells is due to HIV-tat, the cells were incubated with different dilutions of anti-HIV-tat Abs or preimmune serum for 2 h and then examined for the JNK activation. As shown in Figure 3GoB, pretreatment with HIV-tat Abs significantly inhibited the level of JNK activation whereas preimmune serum had no effect. These results thus show that the constitutive JNK activation in HIV-tat gene-transfected cells is due to HIV-tat protein. Furthermore, constitutive JNK activation in HIV-tat-transfected cells was not restricted to H9 cells, since elevated level of JNK activation was also observed in Jurkat and Raji cells transfected with HIV-tat gene (Fig. 3GoC).

The physiologic significance of activation of JNK by HIV-tat protein is not understood. JNK has been shown to increase the transcriptional activity of c-Jun, ATF-2 (activating transcription factor 2), and Elk1 upon their phosphorylation. These transcription factors are the components of AP-1, and so the activation of JNK leads to the activation of AP-1-dependent gene expression (15, 16). We have recently shown that HIV-tat treatment of the cells leads to the increased production of metalloproteinase-9 (MMP-9) and the expression of adhesion molecules (10, 27). The promotor region of both MMP-9 and adhesion molecules contains AP-1 binding sites (28). In the present study we found that HIV-tat caused a time- and dose-dependent activation of the DNA-binding of AP-1 (Fig. 4Go). The activation of AP-1 by HIV-tat thus suggests that one mechanism by which HIV-tat could lead to the increased expression of MMP-9 and adhesion molecules is through the activation of AP-1 in the JNK cascade. HIV-tat has indeed been reported to regulate the expression of a wide variety of other cytokines and their receptors (4, 5, 6, 7, 8, 9), some of which contain AP-1-binding sequence in their promotor region.



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  		FIGURE 4. Effect of HIV-tat treatment on the DNA-binding activity of AP-1. A, U937 cells were treated with 100 ng/ml of HIV-tat for different time intervals. B, U937 cells were treated for 2 h with different concentrations of HIV-tat protein. The nuclear extracts were made, and DNA- binding activity was measured as described in Materials and Methods. The data are representative of two separate replicate experiment.

 
Recent reports also indicate that HIV-tat protein can induce apoptosis in human T cells both by a Fas-Fas ligand-dependent mechanism and by down-modulation of Bcl2 expression (29, 30). McCloskey et al. (1997) have shown that exogenous tat protein induces apoptosis in uninfected T cells, whereas T cells expressing the tat protein were protected from the activation-induced apoptosis (31). The precise nature of signal transduction events induced by HIV-tat that may culminate in apoptosis in T cells is not understood; however, the involvement of JNK in this process cannot be ruled out. Activation of JNK has been observed in cells exposed to a lethal dose of gamma radiation or anti-Fas (32). Further, overexpression of JNK1 caused cell death in transfected cells whereas expression of a dominant-negative mutant of JNK1 blocked gamma radiation-induced cell death (23), suggesting the involvement of this kinase in apoptosis.

Although HIV-tat has been reported to interact with such cell surface molecules as CD26 and integrin {alpha}5ß1 (33, 34), the molecular mechanisms of HIV-tat-mediated cell signaling are not understood. One effector may be oxygen free radicals, whose role in signal transduction of TNF and other cytokines has been extensively described in the literature. Some recent reports indicate that H2O2 plays an important role as a second messenger in signal transduction pathways that regulate the activity of transcription factors such as NF-{kappa}B and AP-1 (35, 36).

To determine whether HIV-tat-mediated activation of JNK involves a reactive oxygen intermediate (ROI), we examined the effects of NAC, a free radical scavenger, on the HIV-tat-mediated activation of JNK. Pretreatment of U937 cells with NAC inhibited the HIV-tat-mediated activation of JNK in a dose-dependent manner (Fig. 5GoA), suggesting the involvement of oxygen free radicals. The effect of NAC was specific since mannitol, a hydroxyl radical quencher, or pyrrolidine dithiocarbamate (PDTC), an iron chelator, had no effect on HIV-tat-induced JNK activation (Fig. 5GoB). Both PDTC and NAC have been previously shown to block NF-{kappa}B activation and transcription of HIV (37, 38). There are other reports, however, that show that PDTC and NAC differentially regulate NF-{kappa}B activation (39). That PDTC and NAC display different effects is in agreement with our results, which show that NAC but not PDTC can block JNK activation. The use of NAC as a novel approach for anti-HIV therapy has also been suggested (40). Thus, overall, our results suggest that HIV-tat activates JNK and AP-1 through an ROI-dependent pathway and that this may play a role in production of cytokines and growth modulation induced by HIV-tat (Fig. 6Go).



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  		FIGURE 5. Effect of N-acetylcysteine (NAC), mannitol, and PDTC on the activation of JNK by HIV-tat. A, U937 cells were pretreated for 30 min with indicated concentrations of NAC at 37°C. B, U937 cells were pretreated with either 5 mM NAC, 50 mM mannitol, or with 100 µM PDTC for 30 min. These cells were then activated with 100 ng/ml of HIV-tat and lysed; we then measured the JNK activity. The data are representative of three separate replicate experiments.

 


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  		FIGURE 6. Possible mechanism of activation of AP-1 by HIV-tat protein. ROI, reactive oxygen intermediate.

 
Our results on the activation of JNK by HIV-tat is in agreement with a recent report of Li et al. (41). These authors examined JNK activation only at 2 h after treatment with HIV-tat and therefore did not find the biphasic activation as shown in our studies. Li et al. also showed that HIV-tat activates MAP kinase; they did not examine MAP kinase kinase (MEK), which we found was not activated. There are seven different MEK reported. Our studies cannot rule out that HIV-tat may activate the MEK that causes the activation of MAP kinase. The transfection of cells with HIV-tat is known to increase IL-2 secretion in response to costimulation with CD3 plus CD28 (42). It is possible that activation of JNK and AP-1 as shown here play a role in IL-2 production. Although more data are required to understand the signal transduction events induced by HIV-tat, the activation of JNK and AP-1 by HIV-tat suggests that it can use this pathway to mediate different cellular responses.


   Acknowledgments
 
We thank Dr. Bing Su for the supply of GST-Jun construct and protein.


   Footnotes
 
1 This work was supported by a grant from the Clayton Foundation of Research. Back

2 Address correspondence and reprint requests to Dr. Bharat B. Aggarwal, Cytokine Research Section, Department of Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030. E-mail address: Back

3 Abbreviations used in this paper: MAP, mitogen-activated protein; JNK, c-Jun N-terminal kinase; AP-1, activator protein-1; NAC, N-acetylcysteine; ROI, reactive oxygen intermediates; PDTC, pyrrolidine dithiocarbamate; MEK, MAP kinase kinase; GST, glutathione S-transferase; MMP-9, matrix metalloproteinase-9. Back

Received for publication December 12, 1997. Accepted for publication March 10, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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