References of "Merville, Marie-Paule"
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See detailChallenges for Biomarker Discovery in Body Fluids Using SELDI-TOF-MS
De Bock, Muriel ULg; De Seny, Dominique ULg; Meuwis, Marie-Alice ULg et al

in Journal of Biomedicine & Biotechnology (2009)

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See detailDeregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells.
Cornez, Isabelle ULg; Creppe, Catherine ULg; Gillard, Magali ULg et al

in Biochemical Pharmacology (2008), 75

Elongator, a multi-subunit complex assembled by the IkappaB kinase-associated protein (IKAP)/hELP1 scaffold protein is involved in transcriptional elongation in the nucleus as well as in tRNA ... [more ▼]

Elongator, a multi-subunit complex assembled by the IkappaB kinase-associated protein (IKAP)/hELP1 scaffold protein is involved in transcriptional elongation in the nucleus as well as in tRNA modifications in the cytoplasm. However, the biological processes regulated by Elongator in human cells only start to be elucidated. Here we demonstrate that IKAP/hELP1 depleted colon cancer-derived cells show enhanced basal expression of some but not all pro-apoptotic p53-dependent genes such as BAX. Moreover, Elongator deficiency causes increased basal and daunomycin-induced expression of the pro-survival serum- and glucocorticoid-induced protein kinase (SGK) gene through a p53-dependent pathway. Thus, our data collectively demonstrate that Elongator deficiency triggers the activation of p53-dependent genes harbouring opposite functions with respect to apoptosis. [less ▲]

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See detailProteomics for prediction and characterization of response to infliximab in Crohn's disease: a pilot study.
Meuwis, Marie-Alice ULg; Fillet, Marianne ULg; Lutteri, Laurence ULg et al

in Clinical Biochemistry (2008), 41(12), 960-7

OBJECTIVES: Infliximab is the first anti-TNFalpha accepted by the Food and Drug Administration for use in inflammatory bowel disease treatment. Few clinical, biological and genetic factors tend to predict ... [more ▼]

OBJECTIVES: Infliximab is the first anti-TNFalpha accepted by the Food and Drug Administration for use in inflammatory bowel disease treatment. Few clinical, biological and genetic factors tend to predict response in Crohn's disease (CD) patient subcategories, none widely predicting response to infliximab. DESIGN AND METHODS: Twenty CD patients showing clinical response or non response to infliximab were used for serum proteomic profiling on Surface Enhanced Lazer Desorption Ionisation-Time of Flight-Mass Spectrometry (SELDI-TOF-MS), each before and after treatment. Univariate and multivariate data analysis were performed for prediction and characterization of response to infliximab. RESULTS: We obtained a model of classification predicting response to treatment and selected relevant potential biomarkers, among which platelet aggregation factor 4 (PF4). We quantified PF4, sCD40L and IL-6 by ELISA for correlation studies. CONCLUSIONS: This first proteomic pilot study on response to infliximab in CD suggests association between platelet metabolism and response to infliximab and requires validation studies on a larger cohort of patients. [less ▲]

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See detailNew biomarkers of Crohn's disease: serum biomarkers and development of diagnostic tools
Meuwis, Marie-Alice ULg; Fillet, Marianne ULg; Chapelle, Jean-Paul ULg et al

in Expert Review of Molecular Diagnostics (2008), 8

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See detailMonomeric calgranulins measured by SELDI-TOF mass spectrometry and calprotectin measured by ELISA as biomarkers in arthritis
De Seny, Dominique ULg; Fillet, Marianne ULg; Ribbens, Clio ULg et al

in Clinical Chemistry (2008), 54

BACKGROUND: SELDI-TOF mass spectrometry (MS) is a high-throughput proteomic approach with potential for identifying novel forms of serum biomarkers of arthritis. METHODS: We used SELDI-TOF MS to analyze ... [more ▼]

BACKGROUND: SELDI-TOF mass spectrometry (MS) is a high-throughput proteomic approach with potential for identifying novel forms of serum biomarkers of arthritis. METHODS: We used SELDI-TOF MS to analyze serum samples from patients with various forms of inflammatory arthritis. Several protein profiles were collected on different Bio-Rad Laboratories ProteinChip arrays (CM10 and IMAC-Cu(2+)) and were evaluated statistically to select potential biomarkers. RESULTS: SELDI-TOF MS analyses identified several calgranulin proteins [S100A8 (calgranulin A), S100A9 (calgranulin B), S100A9*, and S100A12 (calgranulin C)], serum amyloid A (SAA), SAA des-Arg (SAA-R), and SAA des-Arg/des-Ser (SAA-RS) as biomarkers and confirmed the results with other techniques, such as western blotting, immunoprecipitation, and nano-LC-MS/MS. The S100 proteins were all able to significantly differentiate samples from patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from those of patients with inflammatory bowel diseases used as an inflammatory control (IC) group, whereas the SAA, SAA-R, and SAA-RS proteins were not, with the exception of AS. The 4 S100 proteins were coproduced in all of the pathologies and were significantly correlated with the plasma calprotectin concentration; however, these S100 proteins were correlated with the SAA peak intensities only in the RA and IC patient groups. In RA, these S100 proteins (except for S100A12) were significantly correlated with the serum concentrations of C-reactive protein, matrix metalloproteinase 3, and anti-cyclic citrullinated peptide and with the Disease Activity Score (DAS(28)). CONCLUSIONS: The SELDI-TOF MS technology is a powerful approach for analyzing the status of monomeric, truncated, or posttranslationally modified forms of arthritis biomarkers, such as the S100A8, S100A9, S100A12, and SAA proteins. The fact that the SELDI-TOF MS data were correlated with results obtained with the classic calprotectin ELISA test supports the reliability of this new proteomic technique. [less ▲]

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See detailFurther insights in the mechanisms of interleukin-1beta stimulation of osteoprotegerin in osteoblast-like cells
Lambert, Cécile ULg; Oury, Cécile ULg; Dejardin, Emmanuel ULg et al

in Journal of Bone and Mineral Research (2007), 22(9), 1350-1361

The mechanisms of IL-1beta stimulation of OPG were studied in more detail. Whereas p38 and ERK activation was confirmed to be needed, NF-kappaB was not necessary for this regulation. We also found that ... [more ▼]

The mechanisms of IL-1beta stimulation of OPG were studied in more detail. Whereas p38 and ERK activation was confirmed to be needed, NF-kappaB was not necessary for this regulation. We also found that OPG production after IL-1beta stimulation was not sufficient to block TRAIL-induced apoptosis in MG-63 cells. INTRODUCTION: Osteoprotegerin (OPG) plays a key role in the regulation of bone resorption and is stimulated by interleukin (IL)-1beta. Herein, we defined the mechanisms of IL-1beta stimulation of OPG focusing on the potential involvement of MAPK and NF-kappaB. We also examined whether OPG production in response to IL-1beta influences TRAIL-induced apoptosis in MG-63 cells. MATERIALS AND METHODS: OPG mRNA levels in MG-63 cells were quantified by real-time RT-PCR and protein levels of OPG and IL-6 by ELISA. Cell viability was assessed using the methyltetrazidium salt (MTS) reduction assay. The role of the MAPK pathway was studied by both Western blotting and the use of specific chemical inhibitors. NF-kappaB function was studied using BAY 11-7085 and by siRNA transfection to inhibit p65 synthesis. Transcription mechanisms were analyzed by transiently transfecting MG-63 cells with OPG promoter constructs. Post-transcriptional effects were examined by using cycloheximide and actinomycin D. RESULTS: MG-63 cells treatment with IL-1beta resulted in the phosphorylation of c-Jun NH(2)-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). The use of the specific inhibitors showed that p38 and ERK but not JNK were needed for IL-1beta-induced OPG production. In contrast, NF-kappaB was not essential for IL-1beta induction of OPG. We also showed a small transcriptional and a possible post-transcriptional or translational regulation of OPG by IL-1beta. Exogenous OPG blocked TRAIL-induced apoptosis, but IL-1beta induction of OPG did not influence TRAIL-induced cell death. CONCLUSIONS: IL-1beta stimulates OPG production by mechanisms dependent on p38 and ERK. In contrast, NF-kappaB was not essential for this regulation. Although the relevance of IL-1beta stimulation of OPG is still not fully understood, our data showed that IL-1beta stimulation of OPG does not modify TRAIL-induced cell death. [less ▲]

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See detailA role for the transcriptional complex elongator in cell migration and spreading
Creppe, C.; Close, Pierre ULg; Cornez, I. et al

Poster (2007, March)

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See detailBiomarker discovery for inflammatory bowel disease, using proteomic serum profiling
Meuwis, Marie-Alice ULg; Fillet, Marianne ULg; Geurts, Pierre ULg et al

in Biochemical Pharmacology (2007), 73(9), 1422-1433

Crohn's disease and ulcerative colitis known as inflammatory bowel diseases (IBD) are chronic immuno-inflammatory pathologies of the gastrointestinal tract. These diseases are multifactorial, polygenic ... [more ▼]

Crohn's disease and ulcerative colitis known as inflammatory bowel diseases (IBD) are chronic immuno-inflammatory pathologies of the gastrointestinal tract. These diseases are multifactorial, polygenic and of unknown etiology. Clinical presentation is non-specific and diagnosis is based on clinical, endoscopic, radiological and histological criteria. Novel markers are needed to improve early diagnosis and classification of these pathologies. We performed a study with 120 serum samples collected from patients classified in 4 groups (30 Crohn, 30 ulcerative colitis, 30 inflammatory controls and 30 healthy controls) according to accredited criteria. We compared protein sera profiles obtained with a Surface Enhanced Laser Desorption Ionization-Time of Flight-Mass Spectrometer (SELDI-TOF-MS). Data analysis with univariate process and a multivariate statistical method based on multiple decision trees algorithms allowed us to select some potential biomarkers. Four of them were identified by mass spectrometry and antibody based methods. Multivariate analysis generated models that could classify samples with good sensitivity and specificity (minimum 80%) discriminating groups of patients. This analysis was used as a tool to classify peaks according to differences in level on spectra through the four categories of patients. Four biomarkers showing important diagnostic value were purified, identified (PF4, MRP8, FIBA and Hpalpha2) and two of these: PF4 and Hpalpha2 were detected in sera by classical methods. SELDI-TOF-MS technology and use of the multiple decision trees method led to protein biomarker patterns analysis and allowed the selection of potential individual biomarkers. Their downstream identification may reveal to be helpful for IBD classification and etiology understanding. [less ▲]

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See detailTranscriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB
Benoit, Valérie; de Moraes, E.; Dar, N. A. et al

in Oncogene (2006), 25(42), 5708-5718

Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by ... [more ▼]

Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by inducing the binding of nuclear factor-kappaB (NF-kappaB) to its response element in the COX-2 promoter. Inhibition of NF-kappaB prevented p53 induction of Cox-2 expression. Cooperation between p53 and NF-kappaB was required for activation of COX-2 promoter in response to daunomycin, a DNA-damaging agent. Pharmacological inhibition of Cox-2 enhanced apoptosis in response to daunomycin, in particular in cells containing active p53. In esophageal cancer, there was a correlation between Cox-2 expression and wild-type TP53 in Barrett's esophagus (BE) and in adenocarcinoma, but not in squamous cell carcinoma (P < 0.01). These results suggest that p53 and NF-kappaB cooperate in upregulating Cox-2 expression, promoting cell survival in inflammatory precursor lesions such as BE. [less ▲]

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See detailTranscription impairment and cell migration defects in elongator-depleted cells: Implication for familial dysautonomia
Close, Pierre ULg; Hawkes, Nicola; Cornez, Isabelle ULg et al

in Molecular Cell (2006), 22(4), 521-531

Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neuro-developmental disease with complex clinical characteristics. Elongator was previously linked not only ... [more ▼]

Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neuro-developmental disease with complex clinical characteristics. Elongator was previously linked not only with transcriptional elongation and histone acetylation but also with other cellular processes. Here, we used RNA interference (RNAi) and fibroblasts from FD patients to identify Elongator target genes and study the role of Elongator in transcription. Strikingly, whereas Elongator is recruited to both target and nontarget genes, only target genes display histone H3 hypoacetylation and progressively lower RNAPII density through the coding region in FD cells. Interestingly, several target genes encode proteins implicated in cell motility. Indeed, characterization of IKAP/hELP1 RNAi cells, FD fibroblasts, and neuronal cell-derived cells uncovered defects in this cellular function upon Elongator depletion. These results indicate that defects in Elongator function affect transcriptional elongation of several genes and that the ensuing cell motility deficiencies may underlie the neuropathology of FD patients. [less ▲]

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See detailRaloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature.
Olivier, Sabine ULg; Close, Pierre ULg; Castermans, Emilie ULg et al

in Molecular Pharmacology (2006), 69(5), 1615-1623

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of ... [more ▼]

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of multiple myeloma is not well documented. In the present report, we studied the antitumor activity of raloxifene, a selective estrogen receptor modulator, on multiple myeloma cell lines. Raloxifene effects were assessed by tetrazolium salt reduction assay, cell cycle analysis, and Western blotting. Mobility shift assay, immunoprecipitation, chromatin immunoprecipitation assay, and gene expression profiling were performed to characterize the mechanisms of raloxifene-induced activity. Indeed, raloxifene, as well as tamoxifen, decreased JJN-3 and U266 myeloma cell viability and induced caspase-dependent apoptosis. Raloxifene and tamoxifen also increased the cytotoxic response to vincristine and arsenic trioxide. Moreover, raloxifene inhibited constitutive nuclear factor-kappaB (NF-kappaB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor alpha interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-kappaB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1alpha, hgf, pac1,...) and induced the expression of a subset of genes regulating cellular cycle (e.g., p21, gadd34, cyclin G2,...). In conclusion, raloxifene induces myeloma cell cycle arrest and apoptosis partly through NF-kappaB-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells, offering the framework for future studies of selective estrogen receptor modulators therapy in multiple myeloma. [less ▲]

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See detailPeroxisome proliferator-activated receptor-gamma1 is dephosphorylated and degraded during BAY 11-7085-induced synovial fibroblast apoptosis
Relic, Biserka ULg; Benoit, Valerie; Franchimont, Nathalie et al

in Journal of Biological Chemistry (2006), 281(32), 597-604

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR-gamma has ... [more ▼]

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR-gamma has also been demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. As we have previously shown that BAY 11-7085-induced synovial fibroblast apoptosis is prevented by PPAR-gamma agonist 15d-PGJ2; the expression of PPAR-gamma in these cells was studied. Both PPAR-gamma1 and PPAR-gamma2 isoforms were cloned from synovial fibroblast RNA, but only PPAR-gamma1 was detected by Western blot, showing constitutive nuclear expression. Within minutes of BAY 11-7085 treatment, a PPAR-gamma1-specific band was shifted into a form of higher mobility, suggesting dephosphorylation, as confirmed by phosphatase treatment of cell extracts. Of interest, BAY 11-7085-induced PPAR-gamma1 dephosphorylation was followed by PARP and caspase-8 cleavage as well as by PPAR-gamma1 protein degradation. PPAR-gamma1 dephosphorylation was followed by the loss of PPAR-DNA binding activity ubiquitously present in synovial fibroblast nuclear extracts. Unlike the phosphorylated form, dephosphorylated PPAR-gamma1 was found in insoluble membrane cell fraction and was not ubiquitinated before degradation. PPAR-gamma1 dephosphorylation coincided with ERK1/2 phosphorylation that accompanies BAY 11-7085-induced synovial fibroblasts apoptosis. 15d-PGJ2, PGD2, and partially UO126, down-regulated ERK1/2 phosphorylation, protected cells from BAY 11-7085-induced apoptosis, and reversed both PPAR-gamma dephosphorylation and degradation. Furthermore, PPAR-gamma antagonist BADGE induced PPAR-gamma1 degradation, ERK1/2 phosphorylation, and synovial fibroblasts apoptosis. The results presented suggest an anti-apoptotic role for PPAR-gamma1 in synovial fibroblasts. Since apoptotic marker PARP is cleaved after PPAR-gamma1 dephosphorylation but before PPAR-gamma1 degradation, dephosphorylation event might be enough to mediate BAY 11-7085-induced apoptosis in synovial fibroblasts. [less ▲]

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See detailTNFa and IKKb-mediated TANK/I-TRAF phosphorylation: implications for interaction with NEMO/IKKg and NF-kB activation
Bonif, Marianne; Meuwis, Marie-Alice ULg; Close, Pierre ULg et al

in Biochemical Journal (2006), 394

Pro-inflammatory cytokines trigger signalling cascades leading to NF-kappaB (nuclear factor-kappaB)-dependent gene expression through IKK [IkappaB (inhibitory kappaB) kinase]-dependent phosphorylation and ... [more ▼]

Pro-inflammatory cytokines trigger signalling cascades leading to NF-kappaB (nuclear factor-kappaB)-dependent gene expression through IKK [IkappaB (inhibitory kappaB) kinase]-dependent phosphorylation and subsequent degradation of the IkappaB proteins and via induced phosphorylation of p65. These signalling pathways rely on sequentially activated kinases which are assembled by essential and non-enzymatic scaffold proteins into functional complexes. Here, we show that the pro-inflammatory cytokine TNFalpha (tumour necrosis factor alpha) promotes TANK [TRAF (TNF receptor-associated factor) family member associated NF-kappaB activator] recruitment to the IKK complex via a newly characterized C-terminal zinc finger. Moreover, we show that TANK is phosphorylated by IKKbeta upon TNFalpha stimulation and that this modification negatively regulates TANK binding to NEMO (NF-kappaB essential modulator). Interestingly, reduced TANK expression by RNA interference attenuates TNFalpha-mediated induction of a subset of NF-kappaB target genes through decreased p65 transactivation potential. Therefore the scaffold protein TANK is required for the cellular response to TNFalpha by connecting upstream signalling molecules to the IKKs and p65, and its subsequent IKKbeta-mediated phosphorylation may be a mechanism to terminate the TANK-dependent wave of NF-kappaB activation. [less ▲]

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See detailSERMs-induced myeloma cell apoptosis: A study of NF-kappa B inhibition and gene expression signature
Olivier, Sabine ULg; Close, Patricia ULg; Castermans, Emilie ULg et al

in Journal of Bone and Mineral Research (2005, September), 20(9, Suppl. 1), 213

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See detailLow daunomycin concentrations protect colorectal cancer cells from hypoxia-induced apoptosis
Lechanteur, Chantal ULg; Jacobs, Nathalie ULg; Greimers, Roland ULg et al

in Oncogene (2005), 24(10), 1788-1793

Hypoxia, a common feature of solid tumors, is a direct stress that triggers apoptosis in many cell types. Poor or irregular tumor vascularization also leads to a decreased drug diffusion and cancer cells ... [more ▼]

Hypoxia, a common feature of solid tumors, is a direct stress that triggers apoptosis in many cell types. Poor or irregular tumor vascularization also leads to a decreased drug diffusion and cancer cells distant from blood vessels (hypoxic cells) are exposed to low drug concentrations. In this report, we show that low daunomycin concentrations protect HCT116 colorectal cancer cells from hypoxia-induced apoptosis. While hypoxia induced p53 accumulation without expression of its responsive genes (bax and p21), daunomycin treatment restored p53 transactivation activity and cell cycle progression. We also demonstrated a role for Akt activation in daunomycin-induced protection through phosphorylation and inactivation of the Bcl-2 family proapoptotic factor Bad. Our data therefore suggest that chemotherapy could possibly, because of low concentrations in poorly vascularized tumors, protect cancer cells from hypoxia-induced cytotoxicity. [less ▲]

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See detailPhosphorylation of NF-kappa B and I kappa B proteins: implications in cancer and inflammation
Viatour, Patrick ULg; Merville, Marie-Paule ULg; Bours, Vincent ULg et al

in Trends in Biochemical Sciences (2005), 30(1), 43-52

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis. Activation of NF-kappaB mainly occurs via IkappaB kinase ... [more ▼]

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis. Activation of NF-kappaB mainly occurs via IkappaB kinase (IKK)-mediated phosphorylation of inhibitory molecules, including IkappaBalpha. Optimal induction of NF-kappaB target genes also requires phosphorylation of NF-kappaB proteins, such as p65, within their transactivation domain by a variety of kinases in response to distinct stimuli. Whether, and how, phosphorylation modulates the function of other NF-kappaB and IkappaB proteins, such as B-cell lymphoma 3, remains unclear. The identification and characterization of all the kinases known to phosphorylate NF-kappaB and IkappaB proteins are described here. Because deregulation of NF-kappaB and IkappaB phosphorylations is a hallmark of chronic inflammatory diseases and cancer, newly designed drugs targeting these constitutively activated signalling pathways represent promising therapeutic tools. [less ▲]

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See detailProteomic mass spectra classification using decision tree based ensemble methods.
Geurts, Pierre ULg; Fillet, Marianne ULg; De Seny, Dominique ULg et al

in Bioinformatics (2005), 21(14), 3138-45

MOTIVATION: Modern mass spectrometry allows the determination of proteomic fingerprints of body fluids like serum, saliva or urine. These measurements can be used in many medical applications in order to ... [more ▼]

MOTIVATION: Modern mass spectrometry allows the determination of proteomic fingerprints of body fluids like serum, saliva or urine. These measurements can be used in many medical applications in order to diagnose the current state or predict the evolution of a disease. Recent developments in machine learning allow one to exploit such datasets, characterized by small numbers of very high-dimensional samples. RESULTS: We propose a systematic approach based on decision tree ensemble methods, which is used to automatically determine proteomic biomarkers and predictive models. The approach is validated on two datasets of surface-enhanced laser desorption/ionization time of flight measurements, for the diagnosis of rheumatoid arthritis and inflammatory bowel diseases. The results suggest that the methodology can handle a broad class of similar problems. [less ▲]

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See detailInterleukin-6 receptor shedding is enhanced by interleukin-1beta and tumor necrosis factor alpha and is partially mediated by tumor necrosis factor alpha-converting enzyme in osteoblast-like cells.
Franchimont, Nathalie; Lambert, Cécile ULg; Huynen, Pascale ULg et al

in Arthritis and Rheumatism (2005), 52(1), 84-93

OBJECTIVE: Interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions. The goal of the present ... [more ▼]

OBJECTIVE: Interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions. The goal of the present study was to investigate changes in sIL-6R levels in response to the inflammatory cytokines IL-1beta and tumor necrosis factor alpha (TNFalpha) and to determine the role of TNFalpha-converting enzyme (TACE) in this process. METHODS: Levels of sIL-6R in the culture media of MG63 and SAOS-2 osteoblast-like cell lines after exposure to various agents were determined by immunoassay. TACE protein levels were measured by Western immunoblotting. Cells were transfected with small interfering RNA (siRNA) or with an expression plasmid for IL-6R and TACE to determine the potential involvement of TACE in IL-6R shedding. RESULTS: IL-1beta and TNFalpha increased the levels of sIL-6R in the culture media of MG63 osteoblast-like cells. This effect was not influenced by cycloheximide or 5,6-dichlorobenzimidazole riboside but was markedly inhibited by the calcium chelator EGTA and by the TACE and matrix metalloproteinase inhibitor hydroxamate (Ru36156). IL-1beta and TNFalpha had no influence on the alternatively spliced form of IL-6R RNA. Levels of sIL-6R were reduced when MG63 cells were transiently transfected with TACE siRNA. Transfection of SAOS-2 cells with expression plasmids for IL-6R and TACE produced a dose-dependent increase in sIL-6R levels. CONCLUSION: IL-1beta- and TNFalpha-mediated induction of IL-6R shedding in osteoblast-like cells is at least partly dependent on TACE activation. [less ▲]

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