Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts.
Periodontitis is associated with enhanced production of cytokines, prostaglandins and matrix metalloproteinases (MMPs). The aim of this study was to investigate the production and regulation of MMP-1 and MMP-3 in human gingival fibroblasts challenged with the cytokines interleukin-lbeta (IL-1beta), tumor necrosis factor alpha (TNFalpha) or epidermal growth factor (EGF). The results showed that gingival fibroblasts constitutively produce MMP-1 and MMP-3, and that the cytokines IL-1beta, TNFalpha and EGF increase both MMP-1 and MMP-3 production in gingival fibroblasts. The upregulation by the cytokines was apparent at 8 h of incubation and increased thereafter continuously during 48 h of incubation. The upregulation of MMPs, induced by IL-1beta or TNFalpha, was reduced by the cyxlooxygenase-2 (COX-2) inhibitor NS-398, the p38 MAP-kinase inhibitor SB 203580, and the tyrosine kinase inhibitor herbimycin A. In addition, MMP-1 and MMP-3 production, induced by IL-1beta, TNFalpha or EGF, was strongly reduced by the presence of the glucocorticoid dexamethasone. Our findings demonstrate that the cytokines IL-1beta, TNFalpha and EGF, respectively, enhance both MMP-1 and MMP-3 production in human gingival fibroblasts, and that the signal pathways COX-2, MAP-kinases and tyrosine kinases are partly involved in the production of MMPs.
Department of Pediatric Dentistry, Institute of Odontology, Karolinska Institutet, Huddinge, Sweden. Helena.Domeij@ofa.ki.se
Helena
H
Domeij
Tülay
T
Yucel-Lindberg
Thomas
T
Modéer
D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D005881:Gingiva / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology* / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D007375:Interleukin-1; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1