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Synthesis of -Chemokines IP-10, I-TAC, and MIG Are Differentially Regulated in Human Corneal Keratocytes

From the Department of Microbiology and Immunology, College of Medicine, University of South Alabama, Mobile, Alabama.

PURPOSE. Chemokines responsible for recruiting lymphocytes such as activated T cells into the cornea have not been clearly defined. IP-10, I-TAC, and MIG are chemoattractants for these lymphocytes. The goal of this study was to determine whether human corneal keratocyte (HCKs) in culture synthesize these chemokines in response to proinflammatory mediators.

METHODS. HCKs grown in vitro were stimulated with IL-1, TNF-, or IFN-. Induction of -chemokine gene expression was quantitated by real-time PCR and ELISA. Activation of the transcriptional activator STAT1 by IFN- receptors expressed on HCKs was determined by Western blot analysis.

RESULTS. HCKs incubated with TNF-, IL-1, or IFN- resulted in a >2000-fold increase in IP-10 protein secretion by 36 hours after stimulation. In contrast, stimulation with TNF-, IL-1, or IFN- induced levels of MIG and I-TAC that were not significantly greater than constitutive levels. Treatment of HCKs with IFN- activated STAT1 and, in combination with either TNF- or IL-1, enhanced MIG and I-TAC synthesis >20-fold.

CONCLUSIONS. IP-10 synthesis is induced in HCKs by IL-1, TNF-, and IFN-. In contrast, induction of I-TAC and MIG synthesis in HCKs requires costimulation with IFN- and either IL-1 or TNF-. The results suggest therefore, that the upregulation of I-TAC and MIG gene expression at sites of corneal inflammation are more tightly regulated than that of IP-10. A role for differential induction of the three -chemokine genes in corneal inflammatory processes at the eye surface is discussed.

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