A New Mechanism Involving ERK Contributes to Rosiglitazone Inhibition of Tumor Necrosis Factor-α and Interferon-γ Inflammatory Effects in Human Endothelial Cells

Lombardi, A.; Cantini, Giulia; Piscitelli, Elisabetta; Gelmini, Stefania; Francalanci, Michela; Mello, Tommaso; Ceni, E.; Varano, Gabriele; Forti, Gianni; Rotondi, Mario; Galli, Andrea; Serio, Mario; Luconi, Michaela

doi:10.1161/atvbaha.107.160713

Cited by 71 publications

(61 citation statements)

References 39 publications

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“…This result parallels the effect of TZDs on PTC proliferation, but is opposed to the effect of TZDs on CXCL10 secretion, suggesting that other pathways are involved in the chemokine modulation. Regards MAP-kinase ERK1/2, we were unable to show any significant differences either in the level of ERK1/2 phosphorylation or in the amount of not-phosphorylated protein expression between untreated and treated thyroid cells, in contrast to the results obtained in endothelial cells (Lombardi et al 2008).…”

Section: Discussioncontrasting

confidence: 99%

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Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

Antonelli

Ferrari

Fallahi

et al. 2009

Endocrine-Related Cancer

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In papillary thyroid carcinomas (PTCs), oncogenes activate a transcriptional program including the upregulation of CXCL10 chemokine, which stimulates proliferation and invasion. Furthermore, peroxisome proliferator-activated receptor-g (PPARg) activators thiazolidinediones (TZDs) modulate CXCL10 secretion in normal thyroid follicular cells (TFC), and inhibit PTC growth. Until now, no study has evaluated the effect of cytokines on CXCL10 secretion in PTCs, nor the effect of PPARg activation. The combined effects of interferon g (IFNg) and tumor necrosis factor a (TNFa) stimulation on CXCL10 secretion in primary cells from PTCs and TFC were tested. Furthermore, the effect of PPARg activation by TZDs, on CXCL10 secretion and proliferation in these cell types was studied. In primary cultures of TFC and PTCs CXCL10 production was absent under basal conditions; a similar dose-dependent secretion of CXCL10 was induced by IFNg in both cell types. TNFa alone induced a slight but significant CXCL10 secretion only in PTCs. The stimulation with IFNgCTNFa induced a synergistic CXCL10 release in both cell types; however, a secretion more than ten times higher was induced in PTCs. Treatment of TFC with TZDs dose-dependently suppressed IFNgCTNFainduced CXCL10 release, while TZDs stimulated CXCL10 secretion in PTCs. A significant antiproliferative effect by TZDs was observed only in PTCs. In conclusion, a dysregulation of CXCL10 secretion has been shown in PTCs. In fact, a CXCL10 secretion more than ten times higher has been induced by IFNgCTNFa in PTCs with respect to TFC. Moreover, TZDs inhibited CXCL10 secretion in TFC and stimulated it in PTCs. The effect of TZDs on CXCL10 was unrelated to the significant antiproliferative effect in PTCs.

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Section: Discussioncontrasting

confidence: 99%

“…More recently, it has been shown that the TZD effect is not only mediated by activation of the NF-kB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of ERK1/2 (Lombardi et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

Antonelli

Ferrari

Fallahi

et al. 2009

Endocrine-Related Cancer

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“…Rosiglitazone suppresses TNF-a and IFN-g induced phosphorylation of ERK in human microvascular endothelial cells (14), and ERK is known to be required for the induction of some of the cytokines and chemokines examined in this study (49,50). To determine whether TZDs exert their anti-inflammatory action in HASM cells via the suppression of ERK, we assessed the phosphorylation of ERK in cells stimulated with IL-1b in the presence or absence of TZDs ( Figure 4A).…”

Section: Role Of Erk and Nf-kbmentioning

confidence: 97%

“…However, emerging evidence indicates that this class of drugs also has potent antiinflammatory effects. In vitro, these drugs inhibit the release of various cytokines from activated lymphocytes (12), monocytes (13), endothelial cells (14), microglia, and Phorbol 12-myristate 13-acetate-differentiated THP-1 cells (a human monocytic cell line) (15). In vivo, rosiglitazone and pioglitazone also effectively inhibit airway inflammation in various murine models of asthma (16,17).…”

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confidence: 99%

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Zhu¹,

Flynt

Ghosh

et al. 2011

Am J Respir Cell Mol Biol

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Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dosedependently reduced the IL-1b-induced release of IL-6 and vascular endothelial growth factor, the TNF-a-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-a-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-g (PPARg), these anti-inflammatory effects were not affected by a specific PPARg inhibitor (GW 9662) or by the knockdown of PPARg using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the antiinflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARg or AMPK.

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“…Total RNA was reverse transcribed using TaqMan RT PCR kit (Applied Biosystems). Gene expression measurement was performed by TaqMan using the 7900HT Sequence Detection Systems (Applied Biosystems, Foster City, CA, USA) as detailed elsewhere (Lombardi et al 2008). Primers/probes for SDHA (Hs00417200_m1), SDHB (Hs01042482_m1), SDHC (Hs01698067_s1), and SDHD (Hs01098144_g1; TaqMan Gene Expression Assays; Applied Biosystems, Warrington, UK) were used.…”

Section: Rna Isolation and Quantitative Real-time Rt-pcrmentioning

confidence: 99%

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers

Rapizzi¹,

Ercolino²,

Canu³

et al. 2012

Endocrine-Related Cancer

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To date, the consequences of succinate dehydrogenase (SDH) impairment on overall mitochondrial functions are still obscure. In this study, we evaluated SDH activity and expression and mitochondrial homeostasis in 57 tissue samples of pheochromocytoma (PHEO)/ paraganglioma (PGL) obtained from patients genotyped for PHEO/PGL susceptibility genes. The resulted SDH activity and content always decreased in SDH-mutated tumors, in one out of two MAX-mutated patients and in four patients resulted wild type (wt) at genetic screening. All these four wt patients were further screened for large deletions in SDH genes, TMEM127 and MAX and resulted wt but two had somatic SDHD mutations. The RT-PCR in the MAX-mutated sample suggests that the decrease in SDH depends on complex instability and not on a reduced SDHB expression. SDH mutations neither alter citrate synthase (CS) activity nor the content of voltage-dependent anion channel (VDAC) while the expression of the mitochondrial complex IV (cytochrome c oxidase (COX)) was found extremely variable in all (mutated and wt) samples suggesting an impairment of mitochondrial cristae in these tumors. In conclusion, tumors from patients with germ line SDH mutations invariably show decreased enzymatic activity and content, but an SDH impairment may also depend on SDH somatic mutations or, seemingly, on MAX mutations. The impaired SDH activity in the two wt tissues suggests mutations in other still unknown susceptibility genes. Finally, the extreme variability in COX expression levels is yet to be explained and this strongly suggests to evaluate other mitochondrial features to better understand the mitochondrial role in the pathogenesis of these tumors.

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A New Mechanism Involving ERK Contributes to Rosiglitazone Inhibition of Tumor Necrosis Factor-α and Interferon-γ Inflammatory Effects in Human Endothelial Cells

Cited by 71 publications

References 39 publications

Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers

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