Matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 production in human gingival fibroblasts: the role of protein kinase C.
BACKGROUND
Matrix metalloproteinase-1 (MMP-1) plays an important role in tissue remodelling and in the pathology of inflammatory diseases including periodontitis. The activity of MMP-1 is firmly controlled by the endogenous tissue inhibitor of metalloproteinase-1 (TIMP-1).


OBJECTIVE
The aim of the study was to investigate the production and regulation of MMP-1 and TIMP-1 with special regards to the enzyme protein kinase C (PKC) in human gingival fibroblasts.


METHODS
Gingival fibroblasts were treated with substances related to PKC such as phorbol 12-myristate 13-acetate (PMA), interleukin-1beta, Ca2+ -ionophore A231817 and inhibitors of PKC, p38 mitogen-activated protein kinase (p38 MAPK) and tyrosine kinase.


RESULTS
The PKC activator PMA stimulated the production of MMP-1 and TIMP-1 at both the transcriptional and the translational level. The production of MMP-1 and TIMP-1 stimulated by PMA was abolished by the PKC inhibitor bisindolylmaleimide. Treatment of the cells with interleukin-1beta or A23187 synergistically increased the stimulatory effect of PMA on MMP-1 production. In contrast, TIMP-1 production was unaffected by interleukin-1beta and reduced by A23187. Tyrosine kinase inhibitor herbimycin A reduced MMP-1 production induced by PMA, whereas the p38 MAPK-inhibitor SB 203580 synergistically increased the stimulatory effect of PMA on both MMP-1 and TIMP-1 production.


CONCLUSIONS
The present study shows that MMP-1 and TIMP-1 production is regulated differently by interleukin-1beta and calcium in human gingival fibroblasts and that this difference is markedly amplified in the presence of the PKC-activator PMA. Taken together, the discrepancy in the production of MMP-1 and TIMP-1 in gingival fibroblasts may contribute to tissue destruction in periodontal diseases.
Domeij
H
H
Department of Pediatric Dentistry, Institute of Odontology, Karolinska Institutet, Huddinge, Sweden. Helena.Domeij@ofa.ki.se
Modéer
T
T
Yucel-Lindberg
T
T
D000293:Adolescent; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005881:Gingiva / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D007223:Infant; D007375:Interleukin-1 / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
D007375:Interleukin-1; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D011493:Protein Kinase C; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium