title: UVB-mediated induction of cytokines and growth factors in pterygium epithelial cells involves cell surface receptors and intracellular signaling.
abstract: OBJECTIVE
  Pterygium is a proliferative, inflammatory, and invasive ocular surface disease associated with excessive ultraviolet (UV) exposure. This investigation was conducted to identify UV activated signaling pathways in pterygium epithelial cells (PECs) that mediate cytokine and growth factor production and to determine whether these pathways are sensitive to blockade by anti-inflammatory agents such as retinoic acid (RA) and interferon (IFN)-alpha.
  
  
  METHODS
  PECs were pretreated with or without inhibitors of the ERK1/2, JNK, and p38 (PD98059, SB202190, and SB203580, respectively) mitogen-activated protein kinases (MAPK) or with inhibitors of the tyrosine kinase activity of epidermal growth factor receptor (EGFR; PD153035) and platelet-derived growth factor (PDGF; AG1295); exposed to UVB (20 mJ/cm2); and then further treated with the same inhibitors. Media were harvested and analyzed by ELISA for interleukin (IL)-6, IL-8, and vascular endothelial growth factor (VEGF). Cytokine mRNA was assessed by reverse transcription-polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  Inhibitors of ERK1/2, JNK, and p38 MAPKs significantly abolished the UVB-mediated increase in IL-6, IL-8, and VEGF. PD153035 reduced IL-8, AG1295 repressed IL-6, and both inhibitors partially downregulated VEGF production in UV-exposed PECs. RA and IFN-alpha dose dependently abrogated IL-6 and IL-8 but had no effect on VEGF expression after UV exposure.
  
  
  CONCLUSIONS
  The results have identified a stress-induced intracellular pathway and potential cell-surface transmitters that may be relevant to pterygium development. Moreover, two anti-inflammatory/antiangiogenic agents were identified that reduced cytokine production in the study model. Topical application of these drugs may benefit patients with pterygia, potentially reducing the necessity for surgical intervention.
authors.affiliation: Inflammatory Diseases Research Unit, Department of Pathology, School of Medical Sciences, University of New South Wales, Sydney, Australia. n.digirolamo@unsw.edu.au
authors.forename: Nick
authors.initials: N
authors.lastname: Di Girolamo
authors.forename: Denis
authors.initials: D
authors.lastname: Wakefield
authors.forename: Minas T
authors.initials: MT
authors.lastname: Coroneo
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D011625:Pterygium / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology; D014466:Ultraviolet Rays; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D006133:Growth Substances; D016898:Interferon-alpha; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014212:Tretinoin