title: Inhibition of poly(I:C)-induced matrix metalloproteinase expression in human corneal fibroblasts by triptolide.
abstract: OBJECTIVE
  Triptolide is a major component of the herb Tripterygium wilfordii Hook f, extracts of which are used in traditional Chinese medicine, and it has been found to possess immunosuppressive and anti-inflammatory properties. Viral infection of the cornea can lead to corneal ulceration and perforation as a result of collagen degradation in the corneal stroma. We have now examined the effect of triptolide on the expression of matrix metalloproteinases (MMPs) induced by polyinosinic-polycytidylic acid [poly(I:C)], a synthetic analog of viral double-stranded RNA, in cultured human corneal fibroblasts.
  
  
  METHODS
  Human corneal fibroblasts were cultured in the absence or presence of poly(I:C) or triptolide. Secretion of MMPs as well as the phosphorylation of mitogen-activated protein kinases (MAPKs) and the NF-κB-inhibitory protein, IκB-α, were examined by immunoblot analysis. The abundance of MMP mRNAs was determined by reverse transcription and real-time polymerase chain reaction analysis.
  
  
  RESULTS
  Poly(I:C) induced the secretion of MMP-1 and MMP-3 from corneal fibroblasts in a concentration-dependent manner as well as increased the intracellular abundance of MMP-1 and MMP-3 mRNAs. Triptolide inhibited these effects of poly(I:C) on MMP expression in a concentration-dependent manner. The poly(I:C)-induced secretion of MMP-1 and MMP-3 was also attenuated by synthetic inhibitors of MAPK and NF-κB signaling pathways. Triptolide inhibited the poly(I:C)-induced phosphorylation of IκB-α but did not affect that of the MAPKs, Extracellular Signal-Regulated Kinase (ERK), p38MAPK, and c-Jun N-Terminal Kinase (JNK).
  
  
  CONCLUSIONS
  Triptolide inhibited the poly(I:C)-induced production of MMP-1 and MMP-3 by human corneal fibroblasts. Triptolide therefore warrants further investigation as a potential treatment for corneal ulceration associated with viral infection.
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan. k.kimura@yamaguchi-u.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kimura
authors.forename: Norimasa
authors.initials: N
authors.lastname: Nomi
authors.forename: Zhou Hong
authors.initials: ZH
authors.lastname: Yan
authors.forename: Tomoko
authors.initials: T
authors.lastname: Orita
authors.forename: Teruo
authors.initials: T
authors.lastname: Nishida
mesh_terms: D003315:Cornea / Q000166:cytology*; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D011070:Poly I-C / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D016328:NF-kappa B; D010616:Phenanthrenes; D047428:Protein Kinase Inhibitors; C001899:triptolide; D020928:Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D011070:Poly I-C