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Yukiko Kondo, Ken Fukuda, Tadafumi Adachi, Teruo Nishida; Inhibition by a Selective IκB Kinase-2 Inhibitor of Interleukin-1–Induced Collagen Degradation by Corneal Fibroblasts in Three-Dimensional Culture. Invest. Ophthalmol. Vis. Sci. 2008;49(11):4850-4857. doi: 10.1167/iovs.08-1897.
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purpose. Corneal ulcer results from excessive collagen degradation in the corneal stroma. Interleukin (IL)-1 promotes this process by activating signaling molecules that include nuclear factor (NF)-κB and stimulating the synthesis of matrix metalloproteinases (MMPs) in corneal fibroblasts. NF-κB activation is mediated by phosphorylation of the inhibitor IκB by IκB kinase (IKK)-2 and consequent IκB degradation. The authors investigated the effects of the IKK-2 inhibitor [5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1) on collagen degradation by corneal fibroblasts.
methods. Rabbit corneal fibroblasts were cultured in three-dimensional collagen gels. Collagen degradation was evaluated by spectrophotometric quantitation of hydroxyproline in culture supernatants subjected to acid-heat hydrolysis. Expression of MMPs was evaluated by immunoblot analysis, gelatin zymography, and real-time reverse transcription polymerase chain reaction analysis. The phosphorylation and degradation of IκBα and the subcellular localization of NF-κB were examined by immunoblot and immunofluorescence analyses, respectively.
results. IL-1β–induced collagen degradation by corneal fibroblasts was inhibited by TPCA-1 in a concentration- and time-dependent manner. TPCA-1 inhibited the IL-1β–induced expression of MMP-1, -3, and -9 in these cells at both the mRNA and protein levels and the IL-1β–induced activation of pro-MMP-2. In contrast to dexamethasone, TPCA-1 inhibited the phosphorylation and degradation of IκBα and the nuclear translocation of NF-κB induced by IL-1β.
conclusions. An IKK-2 inhibitor blocked IL-1β–induced collagen degradation by corneal fibroblasts by inhibiting the activation of the NF-κB signaling pathway and the upregulation of MMPs. IKK-2 inhibitors are thus potential alternatives to dexamethasone for the treatment of corneal ulcer.
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