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K. Rastogi, B. Govindarajan, S. Spurr-Michaud, M. Gilmore, P. Argueso, I. K. Gipson; Effect of Zinc Metalloproteinase Inhibitors on Streptococcus pneumoniae Induced MUC16 Shedding in Human Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3887.
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Studies from our laboratory show that pathogenic, non-typeable Streptococcus pneumoniae (SPN) strain 168, which causes epidemic conjunctivitis, secretes a protein that induces MUC16 ectodomain shedding from corneal epithelial cells. Previous studies show that various strains of Streptococcus pneumoniae induce syndecan-1 ectodomain shedding from mammary epithelial cells through a zinc metalloproteinase. Different strains of Streptococcus pneumoniae express two to four zinc metalloproteinases including ZmpB, ZmpC, ZmpD, and IgA1. The purpose of this study was to analyze the effect of zinc metalloproteinase inhibitors on MUC16 ectodomain shedding from corneal epithelial cells induced by SPN 168.
Human corneal limbal epithelial cells (HCLE) were cultured for optimal mucin production and treated with 1) exoproducts of non-encapsulated Streptococcus pneumoniae (SPN) strain 168 for one or four hours, 2) metalloproteinase inhibitors, GM6001, TAPI-1, or doxycyline for one hour with/without SPN 168 exoproducts, 3) EDTA or phenanthroline for four hours with/without SPN 168 exoproducts or 4) vehicle controls. Cell culture medium was collected, and released MUC16 content was analyzed by Western blotting. Densitometry was used to quantify the amount of MUC16 ectodomain shedding.
Hydroxamic acids GM6001 and TAPI-1, verified inhibitors of streptococcal ZmpC, showed a 50% decrease in SPN 168 induced MUC16 shedding. Doxycycline, phenanthroline and EDTA, chelators that are inhibitors of IgA1 protease, did not affect SPN 168 induced MUC16 shedding.
Since there is a decrease in MUC16 shedding by SPN 168 in the presence of GM6001 and TAPI-1, ZmpC from SPN 168 may be a MUC16 sheddase. Results with phenanthroline, doxycyline and EDTA indicate that IgA1 protease, secreted by SPN 168, is not involved in induced MUC16 shedding.
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