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Access Type

WSU Access

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Anatomy and Cell Biology

First Advisor

Fu-shin X. Yu

Abstract

The aim of this study was to elucidate the expression and functions of interleukin (IL)-24 and suppressor of cytokine signaling 3 (SOCS3), and their regulatory relationship in C57BL/6 mouse corneas in response to Pseudomonas aeruginosa (PA) infection. Among IL-20R cytokines, only IL-24 was induced at both mRNA and protein levels by the infection, and this upregulation was dampened by flagellin pretreatment. Time course studies revealed that IL-24 expression was markedly elevated, followed by a subsidence and second elevation, a pattern shared with SOCS3 but not IL-1β or IL-6. Silencing of IL-24 enhanced S100A8/A9 expression, and suppressed SOCS3, IL-1β, IL-1RN, and MMP13 expression during an early stage of infection. Downregulation of IL-24 signaling pathway significantly reduced the severity of keratitis, bacterial burden, and neutrophil infiltration; while recombinant IL-24 exacerbated PA keratitis. Furthermore, SOCS3 knockdown impaired the control of PA keratitis. In vitro, while IL-1β induced the expression of SOCS3, IL-24, IL-1β, and IL-6, IL-24 only elicited robust expression of SOCS3 in primarily cultured human corneal epithelial cells. In conclusion, IL-24 promotes PA keratitis by inducing SOCS3 expression, resulting in the suppression of the necessary inflammatory response at an early stage of infection, and in the increased severity of PA keratitis.

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