Epidermal growth factor receptor signaling is partially responsible for the increased matrix metalloproteinase-1 expression in ocular epithelial cells after UVB radiation.
Pterygia are inflammatory, invasive, and proliferative lesions of the human ocular surface in which the matrix metalloproteinase (MMP) collagenase-1 (MMP-1) is highly expressed. Pterygia development may involve MMP-1 activity against interstitial fibrillar collagen, an abundant extracellular matrix component of the cornea, and its induction by ultraviolet light (UVB). We examined the pathways responsible for enhanced expression of MMP-1 in pterygium epithelial cells after UVB exposure and/or treatment with chemical inhibitors of mitogen-activated protein kinases or epidermal growth factor receptor. The induction of MMP-1 by UVB was comparable to that mediated by heparin-binding epidermal growth factor-like growth factor and epidermal growth factor. The epidermal growth factor receptor inhibitor PD153035 partially blocked the UVB-mediated induction of MMP-1 and totally abrogated its production after stimulation with either heparin-binding epidermal growth factor-like growth factor or epidermal growth factor. UVB exposure enhanced the phosphorylated form of ERK1/2 in a time-dependent manner whereas the ERK1/2 inhibitor PD98059 decreased this induction by at least fivefold. Transcripts for c-jun and c-fos were detected as early as 2 hours after UVB exposure and were suppressed by PD98059. The identification of a specific intracellular signaling pathway responsible for the enhanced production of a key enzyme that denatures intact fibrillar collagen has important implications for understanding the pathophysiology and future therapy for pterygia.
Di Girolamo
Nick
N
Inflammatory Diseases Research Unit, Department of Pathology, School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, 2052, Australia. n.digirolamo@unsw.edu.au
Coroneo
Minas
M
Wakefield
Denis
D
D015153:Blotting, Western; D002478:Cells, Cultured; D003228:Conjunctiva / Q000201:enzymology* / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000201:enzymology* / Q000528:radiation effects*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011625:Pterygium / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014466:Ultraviolet Rays
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020781:Matrix Metalloproteinase 1