IL-10/HMOX1 signaling modulates cochlear inflammation via negative regulation of MCP-1/CCL2 expression in cochlear fibrocytes
| Autor: | David J. Lim, Raekil Park, Sung K. Moon, Jeong Im Woo, YooJin Lee, Sejo Oh, Sung Hee Kil |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Cochlear Diseases Immunology Wistar Inflammation CCL2 Biology Response Elements Article Cell Line Mice Downregulation and upregulation Fibrocyte medicine otorhinolaryngologic diseases Immunology and Allergy Gene silencing 2.1 Biological and endogenous factors Animals Humans Aetiology Rats Wistar Chemokine CCL2 Monocyte Transcription Factor RelA Membrane Proteins Cell biology Cochlea Interleukin-10 Rats Interleukin 10 medicine.anatomical_structure Gene Expression Regulation 5.1 Pharmaceuticals Spiral ligament Heme Oxygenase (Decyclizing) medicine.symptom Development of treatments and therapeutic interventions Heme Oxygenase-1 Biotechnology |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950), vol 194, iss 8 |
| Popis: | Cochlear inflammatory diseases, such as tympanogenic labyrinthitis, are associated with acquired sensorineural hearing loss. Although otitis media is extremely frequent in children, tympanogenic labyrinthitis is not commonly observed, which suggests the existence of a potent anti-inflammatory mechanism modulating cochlear inflammation. In this study, we aimed to determine the molecular mechanism involved in cochlear protection from inflammation-mediated tissue damage, focusing on IL-10 and hemoxygenase-1 (HMOX1) signaling. We demonstrated that IL-10Rs are expressed in the cochlear lateral wall of mice and rats, particularly in the spiral ligament fibrocytes (SLFs). The rat SLF cell line was found to inhibit nontypeable Haemophilus influenzae (NTHi)-induced upregulation of monocyte chemotactic protein-1 (MCP-1; CCL2) in response to IL-10. This inhibition was suppressed by silencing IL-10R1 and was mimicked by cobalt Protoporphyrin IX and CO-releasing molecule-2. In addition, IL-10 appeared to suppress monocyte recruitment through reduction of NTHi-induced rat SLF cell line–derived chemoattractants. Silencing of HMOX1 was found to attenuate the inhibitory effect of IL-10 on NTHi-induced MCP-1/CCL2 upregulation. Chromatin immunoprecipitation assays showed that IL-10 inhibits NTHi-induced binding of p65 NF-κB to the distal motif in the promoter region of MCP-1/CCL2, resulting in suppression of NTHi-induced NF-κB activation. Furthermore, IL-10 deficiency appeared to significantly affect cochlear inflammation induced by intratympanic injections of NTHi. Taken together, our results suggest that IL-10/HMOX1 signaling is involved in modulation of cochlear inflammation through inhibition of MCP-1/CCL2 regulation in SLFs, implying a therapeutic potential for a CO-based approach for inflammation-associated cochlear diseases. |
| Databáze: | OpenAIRE |
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