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Failure to Activate Transcription Factor NF-B in Corneal Stromal Cells (Keratocytes)

From the Vision Research Laboratories of New England Medical Center and the Departments of Ophthalmology, and Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.

PURPOSE. Freshly isolated cultures of corneal stromal cells (keratocytes) are incompetent to synthesize the tissue remodeling proteinase, collagenase, in response to agents such as cytochalasin B (CB) or phorbol myristate acetate (PMA), which are strong stimulators of collagenase expression in subcultured fibroblasts of all types, including those from corneal stroma. Incompetence is due to failure to activate an autocrine interleukin (IL)-1 feedback loop required to mediate cell response. The goal of the present study was to investigate the mechanism for this failure.

METHODS. A cell culture model of freshly isolated corneal stromal cells and subcultured stromal fibroblasts from rabbits was used for these studies.

RESULTS. Competence to synthesize collagenase in response to CB was acquired as a differentiation property by corneal stromal cells placed in culture, and did not require subculture. Competence acquisition correlated with transition to a fibroblastic spindle shape, assembly of actin stress fibers, and the acquired capacity to collapse in response to CB. It was demonstrated that competence could be more precisely defined as the capacity to express IL-1 in response to IL-1, making possible activation of the feedback loop. Investigation into the signaling pathway for IL-1 expression in response to IL-1 revealed a requirement for reactive oxygen species and activity of the transcription factor nuclear factor (NF)-B. Importantly, freshly isolated stromal cells were found to be relatively incompetent to activate NF-B in comparison to subcultured stromal fibroblasts.

CONCLUSIONS. Failure to activate NF-B explains incompetence for expression of IL-1 in corneal stromal cells. Because NF-B regulates many cell functions with potential to disturb corneal structure, including expression of inflammatory, stress, and degradative proteinase genes; protection against apoptosis; and cell replication; this seems likely to be an important mechanism protecting corneal stasis and preserving function.

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