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Inhibition by a Selective IB Kinase-2 Inhibitor of Interleukin-1–Induced Collagen Degradation by Corneal Fibroblasts in Three-Dimensional Culture

From the Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan.

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)-B and stimulating the synthesis of matrix metalloproteinases (MMPs) in corneal fibroblasts. NF-B activation is mediated by phosphorylation of the inhibitor IB by IB kinase (IKK)-2 and consequent IB 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 IB and the subcellular localization of NF-B 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 IB and the nuclear translocation of NF-B 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-B signaling pathway and the upregulation of MMPs. IKK-2 inhibitors are thus potential alternatives to dexamethasone for the treatment of corneal ulcer.