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.
Background: Despite its direct connection to the nasopharynx which harbors otitis media pathogens as part of its normal flora, the middle ear cavity is kept free of these bacteria by as yet unknown mechanisms. Respiratory mucosal epithelia, including those of the middle ear and eustachian tube, secrete antimicrobial effectors including lysozyme, lactoferrin and β defensins-1 and -2. To elucidate the role of these innate immune molecules in the normal defense and maintenance of sterility of respiratory mucosa such as that of the middle ear, we assessed their effect on the respiratory pathogens nontypeable Haemophilus influenzae (NTHi) 12, Moraxella catarrhalis 035E, and Streptococcus pneumoniae 3, and 6B.
beta-defensin 2 is produced by a variety of epithelial cell types in the body and exhibits potent antimicrobial activity against a variety of pathogens, including the bacteria that are most commonly associated with otitis media (OM). The human beta-defensin 2 (hBD-2) gene is an NF-kappa B regulated gene and a variety of proinflammatory stimuli can induce its expression. Although the presence of molecules of innate immunity such as lysozyme and lactoferrin has been demonstrated in the middle ear, to date there have been no reports on the expression of beta-defensin 2. In the present study, we demonstrate that beta-defensin 2 is expressed in the middle ear mucosa of humans and rats. We also show that it is expressed in a human middle ear epithelial cell line and that its expression is induced by proinflammatory stimuli such as interleukin 1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF-alpha), and lipopolysaccharide (LPS). Moreover, we demonstrate that the transcriptional activation of hBD-2 gene by IL-1 alpha is mediated through an Src-dependent Raf-MEK1/2-ERK signaling pathway.
Inner ear dysfunction secondary to chronic otitis media (OM), including high-frequency sensorineural hearing loss or vertigo, is not uncommon. Although chronic middle ear inflammation is believed to cause inner ear dysfunction by entry of OM pathogen components or cytokines from the middle ear into the inner ear, the underlying mechanisms are not well understood. Previously, we demonstrated that the spiral ligament fibrocyte (SLF) cell line up-regulates monocyte chemotactic protein 1 (MCP-1) expression after treatment with nontypeable Haemophilus influenzae (NTHI), one of the most common OM pathogens. We hypothesized that the SLF-derived MCP-1 plays a role in inner ear inflammation secondary to OM that is responsible for hearing loss and dizziness. Antibiotics have led to a dramatic decline in the incidence of life-threatening complications of otitis media (OM), such as meningitis or brain abscess (3). However, inner ear dysfunction secondary to chronic OM, including high-frequency sensorineural hearing loss or vertigo, is not uncommon (13,26,36,55,60). Although chronic middle ear inflammation is believed to cause inner ear dysfunction by entry of OM pathogen components or cytokines from the middle ear into the inner ear, the underlying mechanisms are not well understood (18,32,39,44,52,87).The inner ear is a sensory organ for hearing (cochlea) and equilibrium (vestibule). It consists of a variety of specialized cell types (50, 51), such as sensory hair cells, supporting cells, sulcus cells, and spiral ligament fibrocytes (SLFs), which are the most abundant cell types exposed to the perilymph. The type of inner ear cells that respond to proinflammatory signals entering the inner ear remain unknown. Considering that SLFs are one of the abundant cell types in the cochlea and that they secrete cytokines and chemokines after proinflammatory stimuli (72, 97), we hypothesized that the SLFs are major responders to such signals.Preliminary studies of human temporal bones with labyrinthitis showed the infiltration of lysozyme-positive round cells with a monomorphic nucleus into the spiral ligament (unpublished data). Also, SLF cell lines (96) showed an induction in monocyte chemotactic protein 1 (MCP-1) expression after treatment with lysate of nontypeable Haemophilus influenzae (NTHI), one of the most common OM pathogens (72). Moreover, it has previously been shown that monocytes can infiltrate cochlea exhibiting chronic middle ear inflammation or acoustic trauma (22,34,37). These results led us to focus on MCP-1 as an SLF-derived proinflammatory chemokine attracting effector cells and causing inner ear dysfunction.MCP-1, also known as the chemokine C-C motif ligand 2, is produced by various cells, including endothelial cells, smooth muscle cells, fibroblasts, and macrophages, in response to cytokines, growth factors, or bacterial components (9,46,78). It is encoded by an immediate-early gene (33) and is up-regulated by various stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1 (IL-1), tumor necrosis fact...
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