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

Abstract

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.

Epicatechin protects the auditory organ by attenuating cisplatin-induced ototoxicity through inhibition of ERK

“…Important signaling events that regulate the cell death of cisplatin-damaged cochlear cells include: the MAP kinase protein ERK (So et al, 2007), caspases, cytochrome c (Devarajan et al, 2002;Kaushal et al, 2001;Liu et al, 1998;Wang et al, 2004), tumor suppressor p53 (Devarajan et al, 2002;Zhang et al, 2003). MAPKs regulate many cellular events, including differentiation, proliferation, and apoptosis (Cui et al, 2000).…”

“…These findings suggest that the JNK pathway was not involved in cisplatin induced hair cell death but might have played a role in DNA repair and maintenance of cisplatin-damaged sensory cells. ERK activation was critical for the release of preexisting stores of inflammatory cytokines, as well as the delayed production of proinflammatory cytokines by de novo synthesis (So et al, 2007). Proinflammatory cytokines may play a critical role in cisplatin-induced cochlear injury (So et al, 2007).…”

“…ERK activation was critical for the release of preexisting stores of inflammatory cytokines, as well as the delayed production of proinflammatory cytokines by de novo synthesis (So et al, 2007). Proinflammatory cytokines may play a critical role in cisplatin-induced cochlear injury (So et al, 2007). The effects of EC treatment on the expression of MAPKs were investigated in order to determine whether EC blocks the MAPKs signaling pathway mediating the observed apoptotic response.…”

“…Many studies have demonstrated the direct cytotoxic mechanisms of cisplatin including DNA damage (Ries and Klastersky, 1986), mitochondrial dysfunction (Sugiyama et al, 1989), formation of reactive oxygen species (ROS) (Matsushima et al, 1998;Rybak et al, 1999), and inflammatory cytokines (Previati et al, 2007;So et al, 2007). A subset of cell signaling proteins appear to be involved in cisplatin ototoxicity, including the tumor suppressor p53 (Devarajan et al, 2002;Zhang et al, 2003), the MAP kinase protein ERK (So et al, 2007), caspases, and cytochrome c (Devarajan et al, 2002;Kaushal et al, 2001;Liu et al, 1998;Wang et al, 2004).…”

“…A subset of cell signaling proteins appear to be involved in cisplatin ototoxicity, including the tumor suppressor p53 (Devarajan et al, 2002;Zhang et al, 2003), the MAP kinase protein ERK (So et al, 2007), caspases, and cytochrome c (Devarajan et al, 2002;Kaushal et al, 2001;Liu et al, 1998;Wang et al, 2004).…”