title: Epidermal growth factor-induced matrix metalloproteinase-1 expression is negatively regulated by p38 MAPK in human skin fibroblasts.
abstract: BACKGROUND
  Many extracellular stimuli, including epidermal growth factor (EGF), are known to induce MMP-1 expression. Recently, several reports have shown that ERK activity plays an important role in EGF-induced MMP-1 expression. However, EGF is also known to activate many signaling pathways in addition to the ERK pathway, but the roles of these pathways during the induction of MMP-1 by EGF are unclear.
  
  
  OBJECTIVE
  We investigated the role of JNK, p38 MAPK, and PI3K/Akt pathways in EGF-induced MMP-1 expression in human skin fibroblasts. Then, we further explored the inhibitory effect of p38 MAPK pathway on EGF-induced MMP-1 expression and studied the molecular mechanisms involved in the processes.
  
  
  METHODS
  Human skin fibroblasts were pretreated with various chemical inhibitors or small interfering RNA (siRNA) at the indicated concentrations and then treated with EGF, TNF-alpha, or IL-1beta for the indicated times. Protein and mRNA levels of various target molecules were assessed by Western blotting and quantitative real-time PCR, respectively.
  
  
  RESULTS
  We found that EGF-induced MMP-1 expression was positively regulated by JNK as well as ERK but negatively regulated by p38 MAPK in human skin fibroblasts. On the other hand, the PI3K/Akt pathway did not significantly affect MMP-1 induction by EGF. Then we found that the inhibition of p38 MAPK pathway specifically increased the MMP-1 expression stimulated by EGF but not by TNF-alpha or IL-1beta, indicating that the effect of p38 MAPK on MMP-1 expression may be stimulus-type specific in human skin fibroblasts. In addition, the inhibitory effect of p38 MAPK on EGF-induced MMP-1 expression was shown to be mainly mediated by p38-alpha MAPK. Our further studies showed that the inhibition of p38 MAPK but not PI3K specifically increased EGF-induced ERK and JNK activations, and that the augmentation of EGF-induced MMP-1 expression by p38 MAPK inhibition was significantly attenuated by inhibiting the activities of ERK and/or JNK.
  
  
  CONCLUSIONS
  Our results indicate that EGF-induced MMP-1 expression is differentially regulated by the JNK, p38 MAPK, and PI3K/Akt pathways, and suggest that p38 MAPK negatively regulates EGF-induced MMP-1 expression by suppressing the activations of ERK and JNK.
authors.affiliation: Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chi-Hyun
authors.initials: CH
authors.lastname: Park
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Chung
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1