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Originally published In Press as doi:10.1167/iovs.08-1830 on June 19, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4392-4398.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-1830
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Roles of Caspase 1 and Extracellular Signal–Regulated Kinase in Inflammation-Induced Inhibition of Lacrimal Gland Protein Secretion

Driss Zoukhri,1,2 Sunghwan Ko,1 Paul C. Stark,1 and Claire L. Kublin1

1From the Department of General Dentistry, Tufts University School of Dental Medicine, and the 2Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts.

PURPOSE. The purpose of the present study was to investigate the roles of caspase 1 and extracellular signal-regulated kinase (ERK) in inflammation-induced inhibition of lacrimal gland secretion.

METHODS. Lacrimal gland inflammation was induced by injection of lipopolysaccharide (LPS; to study the role of caspase 1) or IL-1β (to study the role of ERK). Lacrimal gland protein secretion was measured using a spectrofluorometric assay. Caspase 1 and ERK activities in the lacrimal gland were measured by immunohistochemistry, Western blotting, or both. Aqueous tear production was measured using phenol red–impregnated cotton threads.

RESULTS. Injection of LPS into the lacrimal gland inhibited neurally and adrenergic agonist–induced protein secretion by 77% and 54%, respectively, and activated caspase 1. The degree of inhibition achieved by LPS was similar to that obtained with injection of IL-1β. Inhibition of caspase 1 alleviated the inhibitory effect of LPS on lacrimal gland secretion. IL-1β activated ERK in the lacrimal gland in vitro and in vivo, and this effect was blocked by UO126, an inhibitor of MEK, the ERK-activating enzyme. IL-1β injection into the lacrimal gland inhibited aqueous tear production by 52% and inhibited neurally and adrenergic agonist-induced protein secretion by 80% and 55%, respectively. UO126 alleviated the inhibitory effect of IL-1β on aqueous tear production and lacrimal gland protein secretion.

CONCLUSIONS. LPS inhibits lacrimal gland secretion by activating caspase 1, and IL-1β activates the ERK pathway to inhibit lacrimal gland protein secretion and aqueous tear production.






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