Abstract

Interleukin-1β (IL-1β) plays a critical mediator in the pathogenesis of eye diseases. The implication of IL-1β in inflammatory responses has been shown to be mediated through up-regulation of inflammatory genes, including matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of IL-1β-induced MMP-9 expression in Statens Seruminstitut Rabbit Corneal Cells (SIRCs) are largely unclear. Here, we demonstrated that in SIRCs, IL-1β induced MMP-9 promoter activity and mRNA expression associated with an increase in the secretion of pro-MMP-9. IL-1β-induced pro-MMP-9 expression and MMP-9 mRNA levels were attenuated by pretreatment with the inhibitor of MEK1/2 (U0126), JNK1/2 (SP600125), NF-κB (Bay11-7082), or AP-1 (Tanshinone IIA) and transfection with siRNA of p42 or JNK2. Moreover, IL-1β markedly stimulated p42/p44 MAPK and JNK1/2 phosphorylation in SIRCs. In addition, IL-1β also enhanced p42/p44 MAPK translocation from the cytosol into the nucleus. On the other hand, IL-1β induced c-Jun and c-Fos mRNA expression, c-Jun phosphorylation, and AP-1 promoter activity. NF-κB translocation, IκBα degradation, and NF-κB promoter activity were also enhanced by IL-1β. Pretreatment with U0126 or SP600125 inhibited IL-1β-induced AP-1 and NF-κB promoter activity, but not NF-κB translocation from the cytosol into the nucleus. Finally, we established that IL-1β could stimulate SIRCs migration via p42/p44 MAPK-, JNK1/2-, AP-1-, and NF-κB-dependent MMP-9 induction. These results suggested that NF-κB and AP-1 activated by JNK1/2 and p42/p44 MAPK cascade are involved in IL-1β-induced MMP-9 expression in SIRCs.

Highlights

  • Dry eye disease is an extremely common ocular disorder, and large epidemiologic studies, using a variety of definitions, have estimated its prevalence at approximate 10% to 20% of the adult population [1]

  • IL-1b acts as a major mediator in the pathogenesis of eye diseases, promoting inflammation, apoptosis, and accumulation of extracellular matrix [1,2]

  • The implication of IL-1b in inflammatory responses has been shown to be mediated through up-regulation of inflammatory genes, including matrix metalloproteinase-9 (MMP-9) [4]

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Summary

Introduction

Dry eye disease is an extremely common ocular disorder, and large epidemiologic studies, using a variety of definitions, have estimated its prevalence at approximate 10% to 20% of the adult population [1]. Dry eye disease can affect visual function, and common tasks of daily living, such as reading, speed, and driving are adversely affected by this condition. Inflammation has been recognized as an important process in these diseases [1]. Interleukin-1b (IL-1b) is one of potent proinflammatory cytokines implicated in tissue damages. IL-1b acts as a major mediator in the pathogenesis of eye diseases, promoting inflammation, apoptosis, and accumulation of extracellular matrix [1,2]. Interleukin-1 receptor-1 (IL-1R1)-deficient mice show attenuated production of ocular surface inflammatory cytokines in experimental dry eyes [3]

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