EGCG blocks TGFβ1-induced CCN2 by suppressing JNK and p38 in buccal fibroblasts

Area of Science:

• Fibrosis research
• Molecular biology
• Cell signaling

Background:

• Oral submucous fibrosis (OSF) is characterized by increased collagen production and decreased matrix degradation, potentially triggered by transforming growth factor β (TGFβ).
• Connective tissue growth factor (CTGF/CCN2) and cyclooxygenase-2 (COX-2) are overexpressed in OSF.
• Understanding the molecular mechanisms of TGFβ-induced CCN2 expression is crucial for developing therapeutic strategies for OSF.

Purpose of the Study:

• To investigate the molecular mechanisms underlying TGFβ-induced CCN2 expression in human buccal mucosal fibroblasts (BMFs).
• To identify potential drug targets for intervention or chemoprevention of OSF.

Main Methods:

• Western blot analysis was used to assess TGFβ-induced CCN2 expression and associated signaling pathways in BMFs.
• Inhibitors of c-Jun NH(2)-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and activin receptor-like kinase 5 (ALK5) were employed.
• The effect of Epigallocatechin-3-gallate (EGCG) on TGFβ1-induced CCN2 synthesis was evaluated.

Main Results:

• TGFβ1 significantly stimulated CCN2 synthesis in BMFs.
• Inhibition of ALK5, JNK, and p38 MAPK pathways significantly reduced TGFβ1-induced CCN2 synthesis.
• EGCG completely blocked TGFβ1-induced CCN2 synthesis by inhibiting JNK and p38 MAPK phosphorylation.
• Prostaglandin E(2) (PGE(2)) did not inhibit TGFβ1-induced CCN2 synthesis in BMFs, unlike in human fetal lung fibroblasts (IMR90).

Conclusions:

• TGFβ1-induced CCN2 synthesis in BMFs is mediated by the ALK5, JNK, and p38 MAPK signaling pathways.
• EGCG effectively suppresses TGFβ1-induced CCN2 synthesis in BMFs by inhibiting JNK and p38.
• The unique signaling pathways in BMFs contribute to PGE(2) resistance, maintaining high CTGF/CCN2 levels in OSF tissues with COX-2.
• EGCG shows promise as a therapeutic agent for controlling OSF.