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

Klinngam, Wannita; Fu, Runzhong; Janga, Srikanth R.; Edman, Maria C.; Hamm-Alvarez, Sarah F.

doi:10.3390/ijms19113530

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

¹,

and

Sarah F. Hamm-Alvarez

^1,2,*

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90007, USA

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.

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

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

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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. https://doi.org/10.3390/ijms19113530

AMA Style

Klinngam W, Fu R, Janga SR, Edman MC, Hamm-Alvarez SF. Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells. International Journal of Molecular Sciences. 2018; 19(11):3530. https://doi.org/10.3390/ijms19113530

Chicago/Turabian Style

Klinngam, Wannita, Runzhong Fu, Srikanth R. Janga, Maria C. Edman, and Sarah F. Hamm-Alvarez. 2018. "Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells" International Journal of Molecular Sciences 19, no. 11: 3530. https://doi.org/10.3390/ijms19113530

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

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