Cytokine Receptor Laboratory
Cytokine Receptor Laboratory
Maia M.,Vesalius Research Center |
Maia M.,Cytokine Receptor Laboratory |
Maia M.,Ghent University |
DeVriese A.,Vesalius Research Center |
And 7 more authors.
BMC Cancer | Year: 2011
Background: Stromal fibroblasts participate in the development of a permissive environment for tumor growth, yet molecular pathways to therapeutically target fibroblasts are poorly defined. CD248, also known as endosialin or tumor endothelial marker 1 (TEM1), is a transmembrane glycoprotein expressed on activated fibroblasts. We recently showed that the cytoplasmic domain of CD248 is important in facilitating an inflammatory response in a mouse model of arthritis. Others have reported that CD248 gene inactivation in mice results in dampened tumor growth. We hypothesized that the conserved cytoplasmic domain of CD248 is important in regulating tumor growth.Methods: Mice lacking the cytoplasmic domain of CD248 (CD248CyD/CyD) were generated and evaluated in tumor models, comparing the findings with wild-type mice (CD248WT/WT).Results: As compared to the response in CD248WT/WTmice, growth of T241 fibrosarcomas and Lewis lung carcinomas was significantly reduced in CD248CyD/CyDmice. Tumor size was similar to that seen with CD248-deficient mice. Conditioned media from CD248CyD/CyDfibroblasts were less effective at supporting T241 fibrosarcoma cell survival. In addition to our previous observation of reduced release of activated matrix metalloproteinase (MMP)-9, CD248CyD/CyDfibroblasts also had impaired PDGF-BB-induced migration and expressed higher transcripts of tumor suppressor factors, transgelin (SM22α), Hes and Hey1.Conclusions: The multiple pathways regulated by the cytoplasmic domain of CD248 highlight its potential as a therapeutic target to treat cancer. © 2011 Maia et al; licensee BioMed Central Ltd.
Deckers J.,Laboratory of Immunoregulation and Mucosal Immunology |
Deckers J.,Ghent University |
Deckers J.,Cytokine Receptor Laboratory |
Branco Madeira F.,Laboratory of Immunoregulation and Mucosal Immunology |
And 3 more authors.
Trends in Immunology | Year: 2013
Asthma is an inflammatory disease of the airways associated with a T helper (Th)2 response. Such a response in the lungs requires complex interactions between innate cells and structural cells. Dendritic cells (DCs) are pivotal during sensitization to allergens but clearly require epithelium-derived signals to become activated. Epithelial cells also contribute to the activation and the survival of mast cells (MCs), basophils, and eosinophils and group 2 innate lymphoid cells (ILC2s). In turn, these innate cells can activate DCs to sustain Th2 immunity. Here, we review the role played by these different populations of immune cells in the pathogenesis of asthma and how they interact to orchestrate Th2 immunity. © 2013 Elsevier Ltd.
Vyncke L.,Cytokine Receptor Laboratory |
Vyncke L.,Ghent University |
Bovijn C.,Cytokine Receptor Laboratory |
Bovijn C.,Ghent University |
And 11 more authors.
Structure | Year: 2016
Members of the Toll-like receptor and interleukin-1 (IL-1) receptor families all signal via Toll/IL-1R (TIR) domain-driven assemblies with adaptors such as MyD88. We here combine the mammalian two-hybrid system MAPPIT and saturation mutagenesis to complement and extend crystallographic and nuclear magnetic resonance data, and reveal how TIR domains interact. We fully delineate the interaction sites on the MyD88 TIR domain for homo-oligomerization and for interaction with Mal and TLR4. Interactions between three sites drive MyD88 homo-oligomerization. The BB-loop interacts with the αE-helix, explaining how BB-loop mimetics inhibit MyD88 signaling. The αC′-helix interacts symmetrically. The MyD88 TIR domains thus assemble into a left-handed helix, compatible with the Myddosome death domain crystal structure. This assembly explains activation of MyD88 by Mal and by an oncogenic mutation, and regulation by phosphorylation. These findings provide a paradigm for the interaction of mammalian TIR domains. © 2016 Elsevier Ltd. All rights reserved.
Vandendriessche B.,Inflammation Research Center |
Vandendriessche B.,Ghent University |
Goethals A.,Inflammation Research Center |
Goethals A.,Ghent University |
And 8 more authors.
BMC Physiology | Year: 2014
Background: MAPK-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to (inflammatory) stress. Among others, MK2 is known to be involved in the regulation of cytokine mRNA metabolism and regulation of actin cytoskeleton dynamics. Previously, MK2-deficient mice were shown to be highly resistant to LPS/d-Galactosamine-induced hepatitis. Additionally, research in various disease models has indicated the kinase as an interesting inhibitory drug target for various acute or chronic inflammatory diseases. Results: We show that in striking contrast to the known resistance of MK2-deficient mice to a challenge with LPS/D-Gal, a low dose of tumor necrosis factor (TNF) causes hyperacute mortality via an oxidative stress driven mechanism. We identified in vivo defects in the stress fiber response in endothelial cells, which could have resulted in reduced resistance of the endothelial barrier to deal with exposure to oxidative stress. In addition, MK2-deficient mice were found to be more sensitive to cecal ligation and puncture-induced sepsis. Conclusions: The capacity of the endothelial barrier to deal with inflammatory and oxidative stress is imperative to allow a regulated immune response and maintain endothelial barrier integrity. Our results indicate that, considering the central role of TNF in pro-inflammatory signaling, therapeutic strategies examining pharmacological inhibition of MK2 should take potentially dangerous side effects at the level of endothelial barrier integrity into account. © 2014 Vandendriessche et al.; licensee BioMed Central Ltd.
Dejager L.,Inflammation Research Center |
Dejager L.,Ghent University |
Dendoncker K.,Inflammation Research Center |
Dendoncker K.,Ghent University |
And 25 more authors.
Mucosal Immunology | Year: 2015
Asthma is a heterogeneous disorder, evidenced by distinct types of inflammation resulting in different responsiveness to therapy with glucocorticoids (GCs). Tumor necrosis factor α (TNFα) is involved in asthma pathogenesis, but anti-TNFα therapies have not proven broadly effective. The effects of anti-TNFα treatment on steroid resistance have never been assessed. We investigated the role of TNFα blockade using etanercept in the responsiveness to GCs in two ovalbumin-based mouse models of airway hyperinflammation. The first model is GC sensitive and T helper type 2 (Th2)/eosinophil driven, whereas the second reflects GC-insensitive, Th1/neutrophil-predominant asthma subphenotypes. We found that TNFα blockade restores the therapeutic effects of GCs in the GC-insensitive model. An adoptive transfer indicated that the TNFα-induced GC insensitivity occurs in the non-myeloid compartment. Early during airway hyperinflammation, mice are GC insensitive specifically at the level of thymic stromal lymphopoietin (Tslp) transcriptional repression, and this insensitivity is reverted when TNFα is neutralized. Interestingly, TSLP knockout mice displayed increased inflammation in the GC-insensitive model, suggesting a limited therapeutic application of TSLP-neutralizing antibodies in subsets of patients suffering from Th2-mediated asthma. In conclusion, we demonstrate that TNFα reduces the responsiveness to GCs in a mouse model of neutrophilic airway inflammation. Thus antagonizing TNFα may offer a new strategy for therapeutic intervention in GC-resistant asthma.
PubMed | Cytokine Receptor Laboratory, Ghent University and Inflammation Research Center
Type: Journal Article | Journal: Mucosal immunology | Year: 2015
Asthma is a heterogeneous disorder, evidenced by distinct types of inflammation resulting in different responsiveness to therapy with glucocorticoids (GCs). Tumor necrosis factor (TNF) is involved in asthma pathogenesis, but anti-TNF therapies have not proven broadly effective. The effects of anti-TNF treatment on steroid resistance have never been assessed. We investigated the role of TNF blockade using etanercept in the responsiveness to GCs in two ovalbumin-based mouse models of airway hyperinflammation. The first model is GC sensitive and T helper type 2 (Th2)/eosinophil driven, whereas the second reflects GC-insensitive, Th1/neutrophil-predominant asthma subphenotypes. We found that TNF blockade restores the therapeutic effects of GCs in the GC-insensitive model. An adoptive transfer indicated that the TNF-induced GC insensitivity occurs in the non-myeloid compartment. Early during airway hyperinflammation, mice are GC insensitive specifically at the level of thymic stromal lymphopoietin (Tslp) transcriptional repression, and this insensitivity is reverted when TNF is neutralized. Interestingly, TSLP knockout mice displayed increased inflammation in the GC-insensitive model, suggesting a limited therapeutic application of TSLP-neutralizing antibodies in subsets of patients suffering from Th2-mediated asthma. In conclusion, we demonstrate that TNF reduces the responsiveness to GCs in a mouse model of neutrophilic airway inflammation. Thus antagonizing TNF may offer a new strategy for therapeutic intervention in GC-resistant asthma.
Beck I.M.,Ghent University |
Beck I.M.,Sloan Kettering Cancer Center |
Drebert Z.J.,Ghent University |
Hoya-Arias R.,Sloan Kettering Cancer Center |
And 30 more authors.
PLoS ONE | Year: 2013
Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1), upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells. © 2013 Beck et al.