RESUMEN
Growing evidence supports the concept that immune reactions occur in the cochlea, where they can function either in protection or as a source of inflammation. Since immunity is generally initiated by antigen presentation of foreign substances to T cells, antigen-presenting cells expressing major histocompatibility complex (MHC) class II molecules are required. Under resting conditions, cochlear cells usually express no MHC class II. However, we show that exposure to -interferon in vitro induces an increase in MHC class II expression in neonatal cochlear cells of mice. In addition, MHC class II immunoreactivity was observed in the inner ear of adult mice after induction of sterile labyrinthitis in vivo. It is concluded that the induction of MHC class II molecules by inflammation may render cochlear cells competent to initiate and participate in immune reactions and may therefore contribute to both immunoprotective and immunopathological responses of the inner ear.
Asunto(s)
Antígenos CD/inmunología , Cóclea/inmunología , Antígenos HLA-D/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Animales , Antivirales/farmacología , Células Cultivadas , Cóclea/metabolismo , Cóclea/patología , Citometría de Flujo/métodos , Glicoproteínas/inmunología , Glicoproteínas/metabolismo , Interferón gamma/farmacología , Laberintitis/inmunología , Laberintitis/metabolismo , Laberintitis/patología , Ratones , Ratones Endogámicos CBA , Órgano Espiral/efectos de los fármacos , Órgano Espiral/inmunología , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/inmunología , Bazo/efectos de los fármacos , Bazo/inmunologíaRESUMEN
OBJECTIVES: Inhibitors of the c-Jun N-terminal kinase (JNK) signaling pathway have been demonstrated to protect hair cells of the auditory system and different types of neurons from various insults, and their use for future therapeutic applications has been proposed. In the study, we evaluated the effects of inhibition of the JNK pathway on process outgrowth from spiral ganglion neurons. METHODS: Spiral ganglion explants from rats (postnatal days 3-5) that were cultured on laminin were treated with neurotrophin-3 and/or the JNK signaling pathway inhibitor CEP-11004. Both neurite length and number of the explants were evaluated and statistically analyzed by analysis of variance. RESULTS: Inhibition of the JNK signaling pathway reduced process outgrowth from spiral ganglion explants. The reduction, both in length and number of neurites, was reversed by the application of neurotrophin-3. CONCLUSIONS: The results indicate that an intact JNK signaling pathway is important for process outgrowth of spiral ganglion neurons. However, neurotrophin-3 stimulates process extension by a JNK independent pathway. Our results demonstrate that inhibition of the JNK pathway can have adverse effects on the extension of spiral ganglion neurons, but that the negative effects can be ameliorated by appropriate treatment.
Asunto(s)
Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuritas/fisiología , Neuronas/fisiología , Ganglio Espiral de la Cóclea/fisiología , Análisis de Varianza , Animales , Técnicas de Cultivo de Célula , Inhibidores Enzimáticos/farmacología , Inmunohistoquímica , Proteínas Quinasas JNK Activadas por Mitógenos , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
The hair cells (HCs) are the most vulnerable elements in the cochlea and damage to them is the most common cause of sensorineural hearing loss. Understanding the intracellular events that lead to the death of HCs is a key to developing protective strategies. Recently, it has been shown that the c-Jun-N-terminal kinase (JNK) pathway is activated in HCs in response to aminoglycosides (J. Neurosci. 20 (2000) 43). We have studied the upstream events leading to JNK activation in aminoglycoside toxicity in vitro. The small GTPases Rac and Cdc42 are well known upstream activators of JNK in other cell types. Clostridium difficile toxin B monoglucosylates all members of the Rho GTPase subfamily (Rho, Rac and Cdc42 isoforms) and inhibits GTP binding by steric interference (Nature 341 (1989) 209). Organ of Corti explants from p5 rat basal turns were maintained in tissue culture and treated with C. difficile toxin B for 12 h. They were then treated with toxin B plus gentamicin for 72 h. Significantly less HC death was observed compared to with gentamicin alone. Toxin B alone had no effect on HCs at the highest concentration used. Using antibodies against phospho-c-Jun, we observed background immunoreactivity in control explants, strong staining of outer hair cell nuclei in gentamicin treated explants, and weaker immunostaining in explants treated with gentamicin and C. difficile toxin B. We conclude that Rho family small GTPases play a role in aminoglycoside toxicity signaling as upstream activators of the JNK signaling pathway.
Asunto(s)
Antibacterianos/toxicidad , Proteínas Bacterianas , Toxinas Bacterianas/farmacología , Inhibidores Enzimáticos/farmacología , Gentamicinas/toxicidad , Células Ciliadas Auditivas Externas/efectos de los fármacos , Proteínas de Unión al GTP rho/antagonistas & inhibidores , Animales , Células Ciliadas Auditivas Externas/enzimología , Células Ciliadas Auditivas Externas/lesiones , Pérdida Auditiva Sensorineural/etiología , Humanos , Técnicas In Vitro , Proteínas Quinasas JNK Activadas por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Proteína de Unión al GTP cdc42/antagonistas & inhibidores , Proteínas de Unión al GTP rac/antagonistas & inhibidoresRESUMEN
Otolaryngologists have long sought to identify causes of sensorineural hearing loss that could be reversed by medical treatment. An increasing amount of clinical and experimental evidence indicates that this postulated entity is related to autoimmune inner ear disease. Because of the lack of well-defined detection methods for identifying autoimmune processes within the human inner ear and the fact that it is one of the few organs of the body not amenable to diagnostic biopsy there has been great interest in developing animal models that mimic clinical entities. Different models will be presented in this paper. The results of these studies should provide sufficient evidence to establish a clear position in mainstream immunology for the entity of autoimmune inner ear disease.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Pérdida Auditiva Sensorineural/inmunología , Linfocitos T/inmunología , Animales , Autoanticuerpos/sangre , Autorradiografía , Western Blotting , Cóclea/inmunología , Cóclea/metabolismo , Oído Interno/inmunología , Cobayas , Humanos , Laberintitis/etiología , Laberintitis/inmunología , Modelos Animales , Ratas , Ratas Endogámicas Lew , Proteínas S100/análisis , Proteínas S100/inmunologíaRESUMEN
There is considerable evidence that hearing and vestibular function can be influenced by immune processes. The inner ear has evolved mechanisms, such as the blood-labyrinthine barrier that limit immune responses and autoimmune processes to reduce the potential for damage to cochlear cells. Recently, expression of Fas ligand (FasL) in some non-lymphoid tissue, as in the anterior chamber of the eye, has been hypothesized to play a role in protection of sensitive organs from activated T-cells. We show that under resting conditions, cochlear cells express little or no FasL. However, after exposure to interferon-gamma in vitro, FasL is induced in many neonatal cochlear cells. In addition, we show that FasL is upregulated in adult cochlear cells after induction of a sterile labyrinthitis in vivo. The induction of FasL by inflammation may serve to limit cochlear immune responses, and to protect sensorineural tissue from immune and autoimmune damage.