title: Protein kinase D1 mediates synergistic MMP-3 expression induced by TNF-α and bradykinin in human colonic myofibroblasts.
abstract: Stromal myofibroblasts regulate extracellular matrix components through the secretion of matrix metalloproteinases such as MMP-3. Both myofibroblasts and MMP-3 have been implicated in colonic inflammation and cancer but the regulatory signaling mechanism(s) are unknown. Exposure of the human colonic myofibroblast cell line 18Co to TNF-α and bradykinin induced synergistic MMP-3 mRNA and protein expression, which were blocked by the preferential PKC inhibitors GF109203X and Go6983 and by the MEK inhibitor U0126. Transfection with siRNA targeting PKD1, a known downstream target of both bradykinin and PKC, completely inhibited MMP-3 mRNA and protein expression. Our results imply that TNF-α and bradykinin amplify MMP-3 expression at a transcriptional level through a signaling cascade involving PKC, PKD1, and MEK. PKD1 plays a critical role in the expression of MMP-3 in human colonic myofibroblasts, and may contribute to the pathophysiology underlying colitis-associated cancer.
authors.affiliation: Departments of Surgery and Medicine, David Geffen School of Medicine, CURE: Digestive Diseases Research Center and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA. jayoo@mednet.ucla.edu
authors.forename: James
authors.initials: J
authors.lastname: Yoo
authors.forename: Citlali Ekaterina
authors.initials: CE
authors.lastname: Rodriguez Perez
authors.forename: Wenxian
authors.initials: W
authors.lastname: Nie
authors.forename: James
authors.initials: J
authors.lastname: Sinnett-Smith
authors.forename: Enrique
authors.initials: E
authors.lastname: Rozengurt
mesh_terms: D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects / Q000201:enzymology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis* / Q000235:genetics; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology*; D009570:Nitriles / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D002070:Butadienes; D007211:Indoles; D008301:Maleimides; D009570:Nitriles; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C089212:protein kinase D; D011493:Protein Kinase C; D019278:Matrix Metalloproteinase 3; C070515:bisindolylmaleimide I; D001920:Bradykinin