Effect of proinflammatory cytokines on cultured spiral ligament fibrocytes

The Journal of Immunology

et al. 2004

Ocular infection with HSV may result in the blinding immunoinflammatory lesion stromal keratitis (SK). This represents a CD4+ T cell-mediated immunopathologic lesion in both humans and a mouse model. Early events in the pathogenesis that set the stage for SK are poorly understood. The present study evaluates the role of IL-1 using a transgenic mouse that overexpresses the IL-1 receptor antagonist (IL-1ra) protein. Such transgenic mice were markedly resistant to SK compared with IL-1ra−/− and C57BL/6 control animals. The resistance was shown to be the consequence of reduced expression of molecules such as IL-6, macrophage-inflammatory protein-2, and vascular endothelial growth factor, normally up-regulated directly or indirectly by IL-1. A critical event impaired in IL-1ra transgenic mice was vascular endothelial growth factor production with a consequent marked reduction in angiogenesis, an essential step in SK pathogenesis. Targeting IL-1 could prove to be a worthwhile therapeutic approach to control SK, an important cause of human blindness.

Section: Discussionsupporting

confidence: 65%

Mice Transgenic for IL-1 Receptor Antagonist Protein Are Resistant to Herpetic Stromal Keratitis: Possible Role for IL-1 in Herpetic Stromal Keratitis Pathogenesis

Biswas

Banerjee

The Journal of Immunology

et al. 2004

“…This result suggests a possibility that there are other cellular sources of inflammatory cytokines in cisplatin ototoxicity in addition to endolymphatic sac and spiral modiolar vein. Furthermore, it has been reported that spiral ligament fibrocytes can secrete chemokines and other inflammatory mediators after stimulation with TNF-a and IL-1b (Yoshida et al 1999), which might induce the infiltration of inflammatory cells and cause cochlear dysfunction because of cochlear inflammation. In this study, we demonstrate that TNF-a is ubiquitously expressed throughout the spiral ligament and stria vascularis after cisplatin injection.…”

Section: Fig 10mentioning

confidence: 99%

“…These results indicate that cisplatin nephrotoxicity is, in part, caused by proinflammatory cytokines and chemokines. In addition, Yoshida et al (1999) reported that proinflammatory cytokines stimulated spiral ligament fibrocytes to produce inflammatory response mediators, including IL-6, TNF-a, MCP-1, KC, MIP-2, sICAM-1, and VEGF. Eventually, the inflammatory mediators induce the infiltration of inflammatory cells, which may prolong the inflammatory response leading to fibrocyte damage and cochlear malfunction.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin Cytotoxicity of Auditory Cells Requires Secretions of Proinflammatory Cytokines via Activation of ERK and NF-κB

Lee

et al. 2007

JARO

219

211

The ototoxicity of cisplatin, a widely used chemotherapeutic agent, involves a number of mechanisms, including perturbation of redox status, increase in lipid peroxidation, and formation of DNA adducts. In this study, we demonstrate that cisplatin increased the early immediate release and de novo synthesis of proinflammatory cytokines, including TNF-a, IL-1b, and IL-6, through the activation of ERK and NF-kB in HEI-OC1 cells, which are conditionally immortalized cochlear cells that express hair cell markers. Both neutralization of proinflammatory cytokines and pharmacologic inhibition of ERK significantly attenuated the death of HEI-OC1 auditory cells caused by cisplatin and proinflammatory cytokines. We also observed a significant increase in the protein and mRNA levels of proinflammatory cytokines in both serum and cochleae of cisplatin-injected rats, which was suppressed by intraperitoneal injection of etanercept, an inhibitor of TNF-a. Immunohistochemical studies revealed that TNF-a expression was mainly located in the spiral ligament, spiral limbus, and the organ of Corti in the cochleae of cisplatin-injected rats. NF-kB protein expression, which overlapped with terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling-positive signal, was very strong in specific regions of the cochleae, including the organ of Corti, spiral ligament, and stria vascularis. These results indicate that proinflammatory cytokines, especially TNF-a, play a central role in the pathophysiology of sensory hair cell damage caused by cisplatin.

“…Multiple studies have demonstrated that the inner ear has the capacity to generate an active immune response [3], thereby resulting in hearing loss in some individuals [4]. Yoshida et al reported that inflammatory response mediators, such as IL-6, TNF-α, MCP-1, KC, MIP-2, sICAM-1 and VEGF, were produced by spiral ligament fibrocytes in response to stimulation with pro-inflammatory cytokines such as IL-1β and TNF-α [5]. Consequently, inflammatory response mediators induce the infiltration of inflammatory cells, which may prolong the inflammatory response and lead to fibrocyte damage and cochlear malfunction.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Lee

et al. 2011

Cell Res

We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4 −/− , but not in STAT6 −/− mice. Moreover, the expression levels of the protein and mRNA of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4 −/− , but not STAT6 −/− mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6 −/− mice were intact after treatment with cisplatin, whereas those from WT and STAT4 −/− mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells, and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Rα1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.