Compound K inhibits MMP‐1 expression through suppression of c‐Src‐dependent ERK activation in TNF‐α‐stimulated dermal fibroblast

• DOI: 10.1111/exd.12536
• Publication Date: 2014-09-02T07:58:09Z
• Authors: Chang Seok Lee; Il‐Hong Bae; Jiwon Han; Gye‐young Choi; Kyung‐Hwan Hwang; Dong‐Hyun Kim; Myeong‐Hun Yeom; Young‐Ho Park; Miyoung Park
• Keywords: Inflammation; 0301 basic medicine; 0303 health sciences; Ginsenosides; Cell Survival; Tumor Necrosis Factor-alpha; JNK Mitogen-Activated Protein Kinases; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Skin Diseases; p38 Mitogen-Activated Protein Kinases; Skin Aging; 3. Good health; CSK Tyrosine-Protein Kinase; ErbB Receptors; 03 medical and health sciences; src-Family Kinases; Cytokines; Humans; Collagen; Matrix Metalloproteinase 1; Cells, Cultured; Signal Transduction; Skin

AbstractCompound K (CK) is one of the major metabolites of ginsenosides exhibiting a variety of pharmacological properties such as anti‐ageing, anti‐oxidation and anti‐inflammatory activities. However, the protective efficacy of CK in abnormal skin conditions with inflammatory responses was not examined. Here, we investigated the effects of CK on matrix metalloproteinase‐1 (MMP‐1) and type I procollagen production in tumor necrosis factor‐α (TNF‐α)‐stimulated human skin fibroblasts HS68 cells and human skin equivalents. We found that CK suppressed MMP‐1 secretion and increased the level of reduced type I procollagen secretion, caused by the inhibition of extracellular signal‐regulated kinase (ERK) activation, but not p38 and c‐Jun N‐terminal kinase (JNK) activation in TNF‐α‐stimulated HS68 cells. Then, we focused on the involvement of the c‐Src and epidermal growth factor receptor (EGFR) as upstream signalling molecules for ERK activation by TNF‐α in HS68 cells. CK suppressed the phosphorylation of c‐Src/EGFR by TNF‐α, which led to the inactivation of downstream signalling molecules including AKT and MEK. In addition, CK suppressed AP‐1 (c‐jun and c‐fos) phosphorylation as downstream transcription factors of active ERK for MMP‐1 expression in TNFα‐stimulated HS68 cells. These results showed novel mechanisms by which CK inhibits TNF‐α‐induced MMP‐1 expression through the inactivation of c‐Src/EGFR‐dependent ERK/AP‐1 signalling pathway, resulting in the inhibition of collagen degradation in human fibroblast cells. Therefore, CK may be a promising protective agent for the treatment of inflammatory skin conditions such as skin ageing and atopic dermatitis.