title: Concanavalin-A triggers inflammatory response through JAK/STAT3 signalling and modulates MT1-MMP regulation of COX-2 in mesenchymal stromal cells.
abstract: Pharmacological targeting of inflammation through STAT3 and NF-κB signaling pathways is, among other inflammatory biomarkers, associated with cyclooxygenase (COX)-2 inhibition and is believed to play a crucial role in prevention and therapy of cancer. Recently, inflammatory factors were found to impact on mesenchymal stromal cells (MSC) contribution to tumor angiogenesis. Given MSC chemotaxis and cell survival are regulated, in part, by the membrane type-1 matrix metalloproteinase (MT1-MMP), an MMP also involved in transducing NF-κB intracellular signaling pathways, we tested whether STAT3 regulation by MT1-MMP may also contribute to the expression balance of COX-2 in MSC. We demonstrate that STAT3 phosphorylation was triggered in MSC treated with the MT1-MMP inducer lectin Concanavalin-A (ConA), and that this phosphorylation was abrogated by the JAK2 inhibitor AG490. MT1-MMP gene silencing significantly inhibited ConA-induced STAT3 phosphorylation and this was correlated with reduced proMMP-2 activation and COX-2 expression. On the other hand, STAT3 gene silencing potentiated ConA-induced COX-2 expression, providing evidence for a new MT1-MMP/JAK/STAT3 signaling axis that may, in part, explain how MT1-MMP contributes to proinflammatory intracellular signaling. Given that MSC are avidly recruited within inflammatory microenvironments and within experimental vascularizing tumors, these mechanistic observations support a possible dual control of cell adaptation to inflammation by MT1-MMP and that may enable MSC to be active participants within inflamed tissues.
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Centre de recherche BIOMED, Département de Chimie, Université du Québec à Montréal, Quebec, Canada H3C 3P8.
authors.forename: Naoufal
authors.initials: N
authors.lastname: Akla
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pratt
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D060833:Cellular Microenvironment / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D003208:Concanavalin A / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C507096:Mmp14 protein, mouse; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D003208:Concanavalin A; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053511:Matrix Metalloproteinase 14