title: MMP-12 induces IL-8/CXCL8 secretion through EGFR and ERK1/2 activation in epithelial cells.
abstract: Macrophage metalloelastase (MMP-12) is described to be involved in pulmonary inflammatory response. To determine the mechanisms linking MMP-12 and inflammation, we examined the effect of recombinant human MMP-12 (rhMMP-12) catalytic domain on IL-8/CXCL8 production in cultured human airway epithelial (A549) cells. Stimulation with rhMMP-12 resulted in a concentration-dependent IL-8/CXCL8 synthesis 6 h later. Similar results were also observed in cultured BEAS-2B bronchial epithelial cells. In A549 cells, synthetic matrix metalloproteinase (MMP) inhibitors prevented rhMMP-12-induced IL-8/CXCL8 release. We further demonstrated that in A549 cells, rhMMP-12 induced transient, peaking at 5 min, activation of ERK1/2. Selective MEK inhibitors (U0126 and PD-98059) blocked both IL-8/CXCL8 release and ERK1/2 phosphorylation. IL-8/CXCL8 induction and ERK1/2 activation were preceded by EGF receptor (EGFR) tyrosine phosphorylation, within 2 min, and reduced by selective EGFR tyrosine kinase inhibitors (AG-1478 and PD168393) by a neutralizing EGFR antibody and by small interfering RNA oligonucleotides directed against EGFR, implicating EGFR activation. In addition, we observed an activation of c-Fos in A549 cells stimulated by rhMMP-12, dependent on ERK1/2. Using small interfering technique, we showed that c-Fos is involved in rhMMP-12-induced IL-8/CXCL8 production. From these results, we conclude that one mechanism, by which MMP-12 induces IL-8/CXCL8 release from the alveolar epithelium, is the EGFR/ERK1/2/activating protein-1 pathway.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U620, Université de Rennes 1, Rennes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Le Quément
authors.forename: Isabelle
authors.initials: I
authors.lastname: Guénon
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Gillon
authors.forename: Vincent
authors.initials: V
authors.lastname: Lagente
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Boichot
mesh_terms: D002460:Cell Line; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016762:Genes, fos / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D053508:Matrix Metalloproteinase 12 / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000166:cytology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D016209:Interleukin-8; C509204:PD168393; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053508:Matrix Metalloproteinase 12