Curcumin inhibits thrombin-stimulated connective tissue growth factor (CTGF/CCN2) production through c-Jun NH2-terminal kinase suppression in human gingival fibroblasts.
BACKGROUND
Connective tissue growth factor (CTGF/CCN2), associated with multiple human fibrotic diseases, is overexpressed in the tissue of gingival overgrowth. Although surgical excision is the current treatment modality for gingival overgrowth, the recurrent rate is high despite proper recall programs. Thrombin plays a key role in wound repair, remodeling, and fibrosis after injury and exerts profibrotic effects by activating protease-activated receptors (PARs). Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a natural plant phenolic compound that possesses both anti-inflammatory and antioxidant properties. This study investigates the signaling pathway of thrombin-induced CCN2 expression and inhibition of CCN2 expression by curcumin.


METHODS
The signaling pathway of thrombin-induced CCN2 expression in human gingival fibroblasts (HGFs) was studied using Western blot analysis. The CCN2 mRNA level was determined by quantitative reverse transcription-polymerase chain reaction.


RESULTS
Thrombin induced CCN2 expression in HGFs by activating PAR1. Pretreatment with antioxidant N-acetyl-l-cysteine, apoptosis signal-regulating kinase 1 (ASK1) inhibitor thioredoxin, and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) significantly reduced thrombin-induced CCN2 expression in HGFs. Curcumin dose dependently inhibited thrombin-induced CCN2 expression through JNK suppression in HGFs.


CONCLUSIONS
The results of this study suggest that thrombin-induced CCN2 expression may occur through PAR1, reactive oxygen species, ASK1, and JNK signaling in HGFs. Curcumin could effectively inhibit CCN2 expression through JNK suppression. These signaling events are important for wound healing and fibrosis. Additional research, including animal studies, is required to confirm the inhibiting role of curcumin in the development of gingival overgrowth.
School of Dentistry, College of Medicine and Department of Dentistry, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
Yi-Wen
YW
Chen
Wan-Hsien
WH
Yang
Man-Ying
MY
Wong
Hao-Hueng
HH
Chang
Mark
M
Yen-Ping Kuo
D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003474:Curcumin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019214:Gingival Overgrowth / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D044462:Receptors, Proteinase-Activated; D055513:Connective Tissue Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D013917:Thrombin; D003474:Curcumin