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Int. J. Mol. Sci. 2018, 19(11), 3530; https://doi.org/10.3390/ijms19113530

Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells

1
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90007, USA
2
Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90007, USA
*
Author to whom correspondence should be addressed.
Received: 31 October 2018 / Accepted: 6 November 2018 / Published: 9 November 2018
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Abstract

Cathepsin S (CTSS) activity is increased in tears of Sjögren’s syndrome (SS) patients. This elevated CTSS may contribute to ocular surface inflammation. Human corneal epithelial cells (HCE-T cells) were treated with recombinant human CTSS at activity comparable to that in SS patient tears for 2, 4, 8, and 24 h. Acute CTSS significantly increased HCE-T cell gene and protein expression of interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) from 2 to 4 h, while matrix metalloproteinase 9 (MMP-9), CTSS, and protease-activated receptor-2 (PAR-2) were increased by chronic CTSS (24 h). To investigate whether the increased pro-inflammatory cytokines and proteases were induced by CTSS activation of PAR-2, HCE-T cells were transfected with PAR-2 siRNA, reducing cellular PAR-2 by 45%. Cells with reduced PAR-2 expression showed significantly reduced release of IL-6, TNF-α, IL-1β, and MMP-9 into culture medium in response to acute CTSS, while IL-6, TNF-α, and MMP-9 were reduced in culture medium, and IL-6 and MMP-9 in cell lysates, after chronic CTSS. Moreover, cells with reduced PAR-2 expression showed reduced ability of chronic CTSS to induce gene expression of pro-inflammatory cytokines and proteases. CTSS activation of PAR-2 may represent a potential therapeutic target for amelioration of ocular surface inflammation in SS patients. View Full-Text
Keywords: Sjögren’s syndrome; Cathepsin S; pro-inflammatory cytokines; proteases; protease-activated receptor-2; matrix metalloproteinase 9; inflammatory dry eye; human corneal epithelial cells; ocular surface inflammation Sjögren’s syndrome; Cathepsin S; pro-inflammatory cytokines; proteases; protease-activated receptor-2; matrix metalloproteinase 9; inflammatory dry eye; human corneal epithelial cells; ocular surface inflammation
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Klinngam, W.; Fu, R.; Janga, S.R.; Edman, M.C.; Hamm-Alvarez, S.F. Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells. Int. J. Mol. Sci. 2018, 19, 3530.

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