Published online before print January 31, 2008, doi: 10.1161/ATVBAHA.107.160713
© 2008 American Heart Association, Inc.
Cell Biology/Signaling |
A New Mechanism Involving ERK Contributes to Rosiglitazone Inhibition of Tumor Necrosis Factor-
and Interferon-
Inflammatory Effects in Human Endothelial Cells
From the DENOthe Center of Excellence for Research, Transfer and High Education: Department of Clinical Physiopathology (A.L., G.C., E.P., S.G., M.F., T.M., E.C., G.V., G.F., M.R., A.G., M.S., M.L.), University of Florence; and the Unit of Internal Medicine and Endocrinology (M.R.), Fondazione Salvatore Maugeri I.R.C.C.S., Pavia, Italy.
Correspondence to Michaela Luconi, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. E-mail m.luconi{at}dfc.unifi.it
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Abstract |
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Objective— Microvascular endothelium is one of the main targets of the inflammatory response. On specific activation, endothelial cells recruit Th1-lymphocytes at the inflammatory site. We investigated the intracellular signaling mediating tumor necrosis factor (TNF)-
and interferon (IFN)-
inflammatory response in human microvascular endothelial cells (HMEC-1) and the interfering effects of the peroxisome-proliferator-activated-receptor (PPAR) agonist, rosiglitazone (RGZ).
Methods and Results— TNF and IFN, mainly when combined, stimulate IFN-inducible protein of 10 kDa (IP10) and fractalkine production evaluated by ELISA and TaqMan analyses. This effect is not only mediated by activation of the NFkB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of extracellular signal-regulated kinases (ERK1/2) as measured by Western blot. RGZ interferes with TNF and IFN stimulation of IP10, fractalkine, and adhesion molecule through a novel rapid mechanism which involves the blocking of ERK activation.
Conclusions— Our findings shed new light on the mechanisms underlying the inflammatory response of microvascular endothelium and on the possible therapeutic use of RGZ in vasculopathies involving Th1-responses.
We demonstrate that TNF and IFN proinflammatory effects, such as upregulation of IP10 secretion, fractalkine, and adhesion molecule expression, are partially prevented by RGZ in human microvascular endothelial cells through a novel rapid nongenomic mechanism involving the ability of this molecule to inhibit ERK activation/phosphorylation.
Key Words: thiazolidinediones • MAPK • CXCL10 • endothelium • Th1-response
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Introduction |
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Tumor necrosis factor (TNF)-
and interferon (IFN)- are the pivotal cytokines coordinating interactions between infiltrating lymphocytes/macrophages and resident cells during the vascular inflammatory Th1-response. Th1-oriented immune responses are implicated in several systemic pathologies such as autoimmune diseases, atherogenesis, type 2 diabetes (T2D), and they also play a major role in the development of acute and chronic rejection as well as in chronic allograft nephropathy.1 IFN, primarily secreted by activated T-lymphocytes, represents the cardinal Th1-cytokine whereas TNF, secreted by monocytes, macrophages, and resident cells, is considered a pleiotropic cytokine involved in a general inflammatory response. Both cytokines modulate the expression of cellular adhesion molecules (CAM) in endothelial cells (ECs). A synergistic action of TNF and IFN in promoting inflammatory response through chemokine secretion has been described.2 In particular, IFN induces ECs to secret CXC chemokines, such as fractalkine, IFN-inducible T-cell -chemoattractant, monokine-induced by IFN and IFN-inducible protein of 10 kDa (IP10). Both IP10 and fractalkine chemoattractant activity is directed toward Th1-lymphocytes.1,3
Thiazolidinediones (TZD) are a pharmacological class of drugs currently used in T2D to improve glucose homeostasis by increasing insulin sensitivity. Besides their well established effects on lipid metabolism and glucose homeostasis, a novel role of TZD in regulating the inflammatory response4 through a direct action on cells of natural and induced immunity is recently emerging, both in vitro and in animal models of human inflammatory disorders.5,6 Experimental evidence suggests that the TZD receptor, PPAR, interferes with cytokine-induced chemokine secretion in monocytes,7 macrophages,8 and venous endothelial cells.9 TZD action seems to be mainly attributable to their ability to bind PPAR, a member of the nuclear hormone receptor family, which acts on specific responsive elements of genes involved in glucose and insulin homeostasis, lipid metabolism, and cellular differentiation. Besides this transactivating activity, a ligand-dependent transcriptional transrepression mechanism has been described, by which activated PPAR represses gene transcription in a DNA-binding independent way through physically sequestering activated transcriptional factors or their coactivators.10 In particular, it has been demonstrated that the antiinflammatory action of some PPAR-ligands, such as rosiglitazone (RGZ), depends on their ability to inhibit chemokine production mainly by suppressing the activity of the proinflammatory transcription factor NFkB. More recently, rapid nongenomic activity of TZD, not resulting in a direct modulation of gene transcription but affecting posttranslational modifications of proteins involved in cell signaling, has been reported.11–15 However, the molecular mechanisms underlying the pharmacological activities of TZD through these alternative pathways remain to be elucidated.
It is known that the 3 mitogen-activated-protein kinase (MAPK) pathways including extracellular signal-regulated kinases 1 and 2 (ERK1/2), JNK, and p38 kinases may be involved in the production of different inflammatory cytokines.16 Moreover, a physical interaction between PPAR and ERKs17 as well as the ERK activator MEK118 seems to negatively regulate the receptor transactivation activity, thus supporting a potential cross-talk between ERK and PPAR signaling.
Taken together, the above data support the hypothesis for a potential application of TZD in the treatment of inflammatory disorders, although a better knowledge of the molecular mechanism of action of these compounds at cellular level is mandatory.
In this light, the aim of the present study was to evaluate the potential intracellular signaling pathways involved in mediating the effects of RGZ on the inflammatory response evoked by TNF and IFN in microvascular ECs.
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Methods |
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For detailed methods, see the supplemental Materials and Methods available online, http://atvb.ahajournals.org. Human microvascular endothelial cells (HMEC-1) were kindly obtained from E. Ades, F.J. Candal (Centers for Disease Control, Atlanta, Ga) and T. Lawley (Emory University). Starved cells were incubated with different stimuli as indicated in the figures.
IP10 secretion was evaluated by ELISA; fractalkine and IP10 expression was quantified by TaqMan analysis. Western and confocal analyses were performed to evaluate protein expression and phosphorylation in 24 h/15 min–treated cells. Thirty nmol/L siRNA was used in silencing experiments. All experiments were performed at least 3 times.
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Results |
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RGZ Inhibits IP10 Secretion Induced by TNF
and IFN in ECsInflammation is characterized by an increased secretion of different cytokines/chemokines, whose balance defines the nature of the inflammatory process. During a Th1-response there is a concomitant production of TNF
and IFN. IP10 secretion induced by a combination of 1 ng/mL TNF and 100 U/mL IFN was inhibited, in a dose-dependent manner, by the simultaneous addition of increasing doses of RGZ (Figure 1A), with a calculated IC50 of 8.85±0.82 µmol/L (coefficient of variation: 9.3%) in agreement with the doses currently used for in vitro studies. RGZ resulted as nontoxic for ECs at all the doses used in IP10 experiments (not shown).
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To investigate the relative contribution of the 2 cytokines on EC response in a Th1-inflammatory context, we also compared IP10 secretion elicited by TNF and IFN used singly or combined. TNF (1 ng/mL) and IFN (100 U/mL) used separately were able to stimulate IP10 secretion, but this effect was dramatically potentiated when the 2 cytokines were combined, thus showing an exponential synergistic effect (Figure 1B). RGZ reduced IP10 secretion in response to both cytokines used alone and together with a similar efficacy.
ERK1/2 Inhibition Mediates the Effect of RGZ on the Inflammatory Response to TNF and IFN
To clarify the intracellular signaling pathways underlying the stimulatory effect of TNF and IFN on IP10 secretion and at which level RGZ exerts its inhibition, we first investigated the 2 main molecular mechanisms described as being involved in mediating the 2 cytokine inflammatory effects, namely the Stat1 and NFkB pathways for IFN and TNF, respectively. IFN and TNF alone and combined stimulated the rapid activation (15 min) of their specific intracellular signaling pathways as expected, which were not altered by RGZ as evaluated by Western blot analysis (supplemental Figure I available online, http://atvb.ahajournals.org). In addition to the rapid activation of Stat1 and NFkB, TNF and IFN, alone and combined, stimulated a rapid phosphorylation/activation of ERK1/2 which was reverted by RGZ (Figure 2A and supplemental Figure II). RGZ effects on these signaling pathways were independent of the time of its addition (supplemental Figure III).
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P<0.001 vs the respective cytokines; D: mean percentage±SE over TNF
The ability of RGZ to inhibit ERK activation in response to TNF and IFN was further confirmed by comparing the effects of RGZ and the MAPK blocker U0126 on ERK phosphorylation. Both RGZ and U0126 blocked ERK1/2 phosphorylation (not shown). HMEC-1 immunofluorescence analysis showed that phospho-ERK, activated by TNF+IFN, localized both in the cytoplasm and in the nucleus and that RGZ inhibited ERK activation to a similar extent as U0126 (Figure 2B). IP10 secretion, elicited by TNF and IFN used singly or combined, was strongly reduced by U0126 (Figure 2C), confirming that ERK signaling is involved in mediating at least part of the 2 cytokine effects on IP10. When combined, RGZ and U0126 further reduced TNF+IFN–induced IP10 secretion compared to when they were used alone (Figure 2D). This additional inhibition could be explained by the fact that, although RGZ converges with U0126 on ERK inactivation, it also exerts an inhibitory effect on other pathways involved in IP10 stimulation (such as the one already demonstrated for NFkB9).
Specificity of ERK signaling in IP10 secretion was further validated by evaluating IP10 stimulation in HMEC-1 transducted with a constitutively active (AdMEK1CA) and a catalytically inactive (AdMEK1CI) MEK1 construct (Figure 3). Even in the absence of TNF+IFN, constitutively activated ERK, obtained through transduction with a MEK1 dominant positive construct, resulted in an upregulation of IP10 mRNA not inhibited by RGZ (Figure 3A). Western blot analysis confirmed that RGZ was not able to revert constitutively activated ERK (Figure 3A).
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The pivotal role of ERK in controlling IP10 expression was further demonstrated by evaluating the effect of transducing a costitutively active or inactive MEK1 on IP10 transcription, in the presence of TNF+IFN (Figure 3B). IP10 expression fold increase over the appropriate TNF+IFN-untreated controls was compared in the 3 groups of transducted cells (Ad, AdMEK1CA, and AdMEK1CI): IP10 stimulation through pathways other than activated ERK results from Figure 3B. In fact, ERK constitutive activation in AdMEK1CA resulted in the inability of TNF+IFN to further stimulate the 2 components of this signaling pathway, the endogenous one and the exogenously transducted, resulting in TNF+IFN modulation of non-ERK pathways only (such as NF
B). Constitutive inactivation of ERK in AdMEK1CI resulted in a dominant negative effect which turned off the endogenous ERK pathway. Again, in this group the TNF+IFN stimulatory effect on IP10 was mediated only by pathways other than ERK. In response to TNF+IFN, MEK1 transduced groups, in which the 2 cytokines were not able to modulate ERK pathway, showed a very low IP10 fold increase compared to the high increase in control Ad group, in which ERK pathway was also activated, further highlighting the importance of ERK in mediating IP10 secretion. In MEK1 transduced groups, RGZ still exerted its inhibitory effect on IP10 expression even though not as strongly as in control Ad group, because of its action only on non-ERK pathways (Figure 3B).
PPAR Is Involved in Mediating RGZ Inhibitory Effect on IP10 Secretion
To investigate the involvement of PPAR in mediating the effects of RGZ on IP10 secretion, we performed the receptor silencing experiments. The receptor silencing resulted in a significant reversion of RGZ inhibition of IP10 secretion elicited by 24-h TNF+IFN-treatment (Figure 4A), suggesting that at least part of RGZ effect is mediated by PPAR. Reversion of RGZ effect by PPAR silencing was not complete, thus not ruling out a PPAR-independent component of RGZ action. Evaluation of both PPAR mRNA and protein was conducted after 24 h TNF+IFN-stimulation in silenced (siRNA) and control (scrambled) cells to validate the silencing procedure (mean±SE PPAR percentage inhibition versus scrambled: mRNA=90.2±2.4, protein=54.2±4.8; n=5, P<0.001 versus scrambled Ctrl). The PPAR-dependent effect of RGZ is further confirmed by the ability of different receptor ligands (ciglitazone, pioglitazone, and the nonglitazonic GW1929) to inhibit IP10 secretion to a similar extent as RGZ (Figure 4B).
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RGZ Antiinflammatory Activity Is Not Limited to IP10 Inhibition: Effect on Adhesion Molecules and Fractalkine
CAM expression is influenced by the cytokine milieu of ECs and their upregulation by TNF and IFN treatment in vitro has already been demonstrated.19 RGZ reverted the increased expression of both vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule-1 (ICAM)-1 to a similar extent as U0126 in HMEC-1 treated 24 h with TNF and IFN (supplemental Figure IV).
Besides IP10, another Th1-polarizing chemokine, fractalkine, is upregulated in ECs in response to TNF and IFN.20 Similarly to what we found for IP10, 24-h treatment of cells with 1 ng/mL TNF and 100 U/mL IFN stimulated fractalkine transcription as evaluated by TaqMan analysis and again their action synergized, similarly to what we found for IP10 (fractalkine mRNA fold increase over Ctrl±SE, n=3: TNF=973.6±289.9, P<0.01 versus Ctrl; IFN=33.1± 11.8, P<0.05 versus Ctrl; TNF+IFN=31048±5460, P<0.001 versus Ctrl). Concomitant addition of 10 µmol/L RGZ or 25 µmol/L U0126 reverted this effect (fractalkine expression percentage inhibition, n=3: RGZ % inhibition over TNF=70.3±18.6, P<0.01; over IFN=75.6±20.8, P<0.05; over TNF+IFN=76.0±9.8, P<0.001 and U0126 % inhibition over TNF=86.1±2.3, P<0.001; over IFN=93.9±0.6, P<0.001; over TNF+IFN=78.1±1.4, P<0.001). RGZ inhibition of TNF+IFN-induced fractalkine expression was confirmed by Western blot analysis using a specific antibody to detect fractalkine in total cell lysates (supplemental Figure V).
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Discussion |
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Endothelial response to inflammation plays a pivotal role in the early steps of the development of chronic pathologies. Endothelial dysfunction is a crucial and potentially treatable stage in the multifactorial process of graft vasculopathy and rejection, as well as autoimmune diseases, atherogenesis, T2D, and other metabolic disorders. TNF
and IFN produced at high levels at the inflammatory site act on ECs to modulate the evolution of the inflammatory response and the entity of the endothelial damage. We set up an in vitro model of human microvascular ECs to study the intracellular mechanisms involved in mediating endothelial response to inflammatory stimuli and the potential RGZ effects. We report that:
- In addition to the well known activation of Stat1 and NFkB signaling pathways, a further mechanism represented by rapid phosphorylation/activation of ERK1/2 is involved in mediating TNF- and IFN-induction Th1-proinflammatory cytokines, including IP10 and fractalkine, as well as in stimulating CAM expression;
- RGZ antiinflammatory effect, resulting from inhibition of TNF- and IFN-induced secretion of IP10, fractalkine, and CAM, is partially mediated by a novel rapid mechanism which reverts ERK phosphorylation/activation.
IP10 secretion drives a Th1-inflammatory response in which the recruited CD4+ T-lymphocytes produce IFN. In turn, a positive loop is established between recruited Th1 and ECs stimulated by IFN. Not only does IP10 mediate lymphocyte recruitment, but it also drives T-cell proliferation and IFN secretion.1 TNF alone is also able to elicit IP10 secretion from HMEC-1, suggesting that this phenomenon could contribute to initiating Th1-recruitment at the site of inflammation.
Our results demonstrate that TNF and IFN converge on a rapid activation of ERK. ERK phosphorylation is deeply involved in stimulating IP10 secretion in response to the 2 cytokines, because this phenomenon is partially reverted by the inhibition of MEK1 activity. Although the MAPK kinase signaling has been described to mediate some of the effects on cytokine production elicited by IFN and TNF,16 this is the first report demonstrating that ERK activation mediates IP10 secretion induced by TNF and IFN. Indeed, very little is known about the intracellular signaling underlying this phenomenon. TNF induces IP10 secretion in mast cells but through NFkB and p38-MAPK pathways, not involving ERK,21 whereas IFN-induced IP10 synthesis is suppressed by Stat1 inhibition.22
The anti-inflammatory effects of PPAR ligands, evaluated as the ability of TZD to inhibit IFN proinflammatory effects, have been previously investigated in vasculopathies.5 Although currently published studies suggest that the antiinflammatory action of TZD can be mediated both in vivo23–25 and in vitro9 by their ability to interfere with the transcriptional activity of NFB, the intracellular mechanisms underlying such effects might not be yet fully clarified. Here, we demonstrate that RGZ inhibits in a dose-dependent manner IP10 secretion in response to TNF and IFN by interfering with the rapid ERK1/2 activation induced by the 2 cytokines. RGZ interference with intracellular TNF and IFN signaling other than ERK cannot be excluded, although it is not mediated by an effect on IkB degradation and Stat1 phosphorylation. The role of ERK1/2 inhibition is further supported by the ability of U0126 to suppress TNF+IFN-stimulated IP10 production and by RGZ inability to revert IP10 production in constitutively active MEK1 transducted HMEC-1. All together these findings allow us to propose that the interference with the NFkB pathway could not be the only mechanism supporting the beneficial effects of TZD on the inflammatory response in microvascular endothelium. This is the first time that PPAR ligands have been shown to inhibit ERK activation, however MEK and ERK have been described as directly interacting with PPAR to inhibit its transcriptional activity.18 Moreover, nongenomic effects of TZD have already been described on rapid activation of different protein kinases.11,26 In particular, RGZ has been reported to rapidly inhibit ERK1/2 and p38-MAPK phosphorylation induced by homocysteine.27
Although the mechanism by which PPAR ligands block ERK phosphorylation in HMEC-1 remains to be elucidated, a direct interaction of the receptor with activating kinases upstream of ERKs or an activation of ERK phosphatases could be reasonably hypothesized. The direct involvement of the receptor in mediating RGZ action is strongly supported by the results of silencing experiments and by IP10 secretion inhibition exerted by other PPAR ligands. However, because receptor silencing does not completely revert RGZ effect, a small component of nonreceptorial mechanism cannot be ruled out.
Similarly to what we found for IP10, we demonstrated that also fractalkine regulation is under the control of rapid ERK activation/phosphorylation. Fractalkine is a unique chemokine expressed on proinflammatory cytokine-activated ECs, which functions not only as a chemo-attractant but also as an adhesion molecule for Th1- but not Th2-polarized lymphocytes.3 Interestingly, fractalkine can act on endothelium in an autocrine loop, stimulating angiogenesis and vascular inflammation through direct activation of ERK/PI3K pathways,28 thus amplifying the circuit of inflammation/Th1 polarization. Both IP10 and fractalkine seem to play a pivotal role in the immune response regulating acute and chronic graft rejection. Indeed, their expression is significantly increased in rejecting but not in nonrejecting grafts29,30 and similarly, the 2 mice systems with targeted disruption of CXCR3 and its ligand31,32 or of fractalkine receptor CX3CR1,33 show a significantly increased graft survival.
Endothelial dysfunctions and consequent transplant atherosclerosis are commonly observed in kidney and heart graft recipients and play a main role in graft loss.34,35 The etiology of this allograft endothelial alteration is multifactorial and may include preexisting atherosclerosis of the graft vessels, reperfusion injury during transplantation. Moreover, ECs orchestrate the immune response underlying the process of rejection, through active cytokine/chemokine release and interaction with immunocytes.
Taking into account that graft rejection involves a Th1-polarized response,36 inhibition of such a polarization using pharmacological tools represents a valid therapeutic approach to improve graft and patient survival rates. In this scenario, our data strongly suggest that RGZ acts on ECs to dampen the Th1-polarizing evocated inflammatory response, specifically interfering with IP10 and fractalkine secretion, thus representing a potential drug to be used in immunosuppression therapy for allografts. Interestingly, animal treatment with the TZD pioglitazone has recently been demonstrated to prevent acute and chronic rejection of heart transplant through suppression of inflammatory cytokines secretion and smooth muscle cell proliferation.37 Our findings could further explain the beneficial TZD effects in the light of a direct anti-Th1 inflammatory action on the microvascular endothelium. However, the recently emerging discussion on the potential cardiovascular risk associated with the use of RGZ in diabetic patients which followed Nissen & Wolsky’s article and the interim report on RECORD trial,38,39 raises substantial uncertainty about the complete cardiovascular safety of the use of this drug, at least in the diabetic population. Conclusive results are nevertheless far away because of the limits of the experimental and meta-analysis studies conducted so far.
In summary, we demonstrate that the rapid ERK activation represents an adjunctive novel pivotal signaling for the inflammatory response evoked in microvascular endothelium by TNF and IFN and that RGZ is able to significantly inhibit this signaling cascade. Our results suggest that RGZ may be a promising antiinflammatory drug and that it may be worth testing its addition to immunosuppression protocols used in graft recipients to prevent endothelial dysfunction driving graft rejection.
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Acknowledgments |
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We thank Prof Paola Romagnani (University of Florence, Italy) for her contribution and Prof Marco Foschi (University of Florence, Italy) for his gift of MEK constructs.
Sources of Funding
This study has been supported by the Tuscany REgional Study On Rosiglitazone project (TRESOR).
Disclosures
None.
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Footnotes |
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Original received July 24, 2007; final version accepted January 10, 2008.
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