IOVS Hypertension
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Originally published In Press as doi:10.1167/iovs.08-1873 on May 16, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3992-3998.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-1873
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Regulation of the Receptor for TNF{alpha}, TNFR1, in Human Conjunctival Epithelial Cells

Ellen B. Cook,1,2 James L. Stahl,1,2 Frank M. Graziano,1 and Neal P. Barney3

1From the Departments of Medicine and 3Ophthalmology and Visual Sciences, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin.

PURPOSE. Previous studies demonstrated that mast cell–derived TNF{alpha} stimulation is critical to the upregulation of intercellular adhesion molecule (ICAM)-1 on human conjunctival epithelial cells (HCECs), which is an important feature of ocular allergic inflammation. Shedding of TNFR1 by TNF{alpha}-converting enzyme (TACE) is a primary mechanism for the regulation of TNF{alpha}-mediated events. This process has not been examined in HCECs. In this study, the authors examined the regulation of TNFR1 expression and shedding by TACE on primary HCECs and the IOBA-NHC conjunctival epithelial cell line.

METHODS. Primary human conjunctival mast cells and epithelial cells were obtained from cadaveric conjunctival tissue. HCECs were incubated with and without activators (IgE-activated mast cell supernates, phorbol myristate acetate [PMA; to activate TACE], TNF{alpha}, and IFN{gamma} [to upregulate TNFR1]) for 24 hours. Pretreatment with the TACE inhibitor TAPI-2 was used to inhibit shedding of TNFR1. Supernates collected from the incubations were analyzed with ELISA for soluble TNFR1 (sTNFR1). With the use of flow cytometry, cells were harvested from these experiments for analysis of TNFR1 and ICAM-1 receptor expression.

RESULTS. IgE-activated conjunctival mast cell supernates upregulated the expression of TNFR1. TAPI-2 inhibited the PMA-induced release of sTNFR1 receptor and enhanced the surface expression of TNFR1 in HCECs in a dose-dependent manner. Upregulation of TNFR1 expression by priming with TAPI-2 and IFN{gamma} resulted in enhanced ICAM-1 expression in response to TNF{alpha} stimulation (significant change in the slope of the dose–response curve).

CONCLUSIONS. These results demonstrate that TACE promotes TNFR1 shedding in HCECs and that TNFR1 expression may be a more significant target than TNF{alpha} for intervention in ocular inflammation.






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