title: Compound K inhibits MMP-1 expression through suppression of c-Src-dependent ERK activation in TNF-α-stimulated dermal fibroblast.
abstract: Compound 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.
authors.affiliation: Medical Beauty Research Institute, Amorepacific Corporation R&D Center, Yongin, Korea.
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Lee
authors.forename: Il-Hong
authors.initials: IH
authors.lastname: Bae
authors.forename: Jiwon
authors.initials: J
authors.lastname: Han
authors.forename: Gye-young
authors.initials: GY
authors.lastname: Choi
authors.forename: Kyung-Hwan
authors.initials: KH
authors.lastname: Hwang
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Myeong-Hun
authors.initials: MH
authors.lastname: Yeom
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Miyoung
authors.initials: M
authors.lastname: Park
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D002470:Cell Survival; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D036145:Ginsenosides / Q000737:chemistry*; D006801:Humans; D007249:Inflammation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism*; D015595:Skin Aging; D012871:Skin Diseases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D003094:Collagen; D016207:Cytokines; D066246:ErbB Receptors; D036145:Ginsenosides; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases; C112772:ginsenoside compound K; C512478:EGFR protein, human; C000631346:CSK protein, human; C522360:MMP1 protein, human
keywords: compound K; fibroblasts; matrix metalloproteinase-1; tumor necrosis factor-α