title: Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo.
abstract: This study was to investigate the role of macrophage migration inhibitory factor (MIF) in mouse acute otitis media (AOM), we hypothesize that blocking MIF activity will relieve mouse AOM. A mouse AOM model was constructed by injecting lipopolysaccharide (LPS) into the middle ear of C57BL/6 mice through the tympanic membrane (TM). MIF levels were measured by real-time PCR (RT-PCR) and ELISA after LPS application. Normal or AOM mice were given PBS or ISO-1 (MIF antagonist) every day for 10 days and the hearing levels were determined by measuring auditory brainstem response (ABR) threshold. After the ABR test finished, H&E staining was conducted and the inflammation was also measured by detecting interleukin (IL)-1β, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels with RT-PCR and ELISA. TLR-4 expression was determined by western blotting and NF-κB activation was determined by electrophoretic mobility shift assays. Compared with the normal control, MIF levels in the middle ear of LPS-induced AOM mice were significant increased. The ABR results showed that mean ABR thresholds in ISO-1 treated AOM mice were significantly reduced compared with PBS treated AOM mice since day 7, indicating that ISO-1 treatment potentially improved the hearing levels of AOM mice. H&E staining showed that ISO-1 treatment could reduce the mucosal thickness of AOM mice. In ISO-1 treated mice, TLR-4 expression and levels of IL-1β, TNF-α and VEGF were significantly lower compared with PBS treated AOM mice. ISO-1 treatment also significantly inhibited NF-κB activation in AOM mice compared with PBS treated AOM mice. These results suggested that blocking the activity of MIF by ISO-1 could reduce the inflammation in AOM mice in which process TLR-4 and NF-κB were involved. The reduction in MIF activity is conducive to alleviate mouse AOM, which may serve as a potential therapeutic target for the treatment of AOM.
authors.affiliation: Department of Otorhinolaryngology-HNS, The Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an 710049, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Otorhinolaryngology-HNS, The Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an 710049, China. Electronic address: minxu_first@163.com.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Qingyin
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Otorhinolaryngology-HNS, The Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an 710049, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Otorhinolaryngology-HNS, The Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an 710049, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Zhaoqiang
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001309:Auditory Threshold; D016057:Evoked Potentials, Auditory, Brain Stem; D007555:Isoxazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010033:Otitis Media / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D007555:Isoxazoles; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D051197:Toll-Like Receptor 4
keywords: AOM; IL-1β; ISO-1; MIF; TNF-α; VEGF
references.citation: J Mol Med (Berl). 1998 Mar;76(3-4):151-61
references.pmid: 9535548
references.citation: Drug News Perspect. 2010 May;23(4):257-64
references.pmid: 20520854
references.citation: Science. 1989 Dec 8;246(4935):1306-9
references.pmid: 2479986
references.citation: Infect Immun. 1997 Nov;65(11):4431-5
references.pmid: 9353016
references.citation: J Exp Med. 1994 Jun 1;179(6):1895-902
references.pmid: 8195715
references.citation: Mol Med. 1996 Jan;2(1):143-9
references.pmid: 8900542
references.citation: Acta Otolaryngol. 2003 Jun;123(5):559-63
references.pmid: 12875575
references.citation: Audiol Neurootol. 2012;17(3):148-54
references.pmid: 22104377
references.citation: Eur J Pharmacol. 2007 Jul 12;567(1-2):19-25
references.pmid: 17499239
references.citation: J Mol Biol. 1998 Jul 3;280(1):85-102
references.pmid: 9653033
references.citation: Lancet Infect Dis. 2010 Mar;10(3):195-203
references.pmid: 20185098
references.citation: Acta Otolaryngol. 2008 Jul;128(7):750-5
references.pmid: 18568516
references.citation: Annu Rev Immunol. 2003;21:335-76
references.pmid: 12524386
references.citation: Clin Diagn Lab Immunol. 2003 May;10(3):417-22
references.pmid: 12738641
references.citation: J Biol Chem. 2004 Aug 27;279(35):36171-4
references.pmid: 15226292
references.citation: Auris Nasus Larynx. 2011 Jun;38(3):319-24
references.pmid: 21227609
references.citation: Curr Allergy Asthma Rep. 2011 Dec;11(6):499-507
references.pmid: 21901304
references.citation: Int J Pediatr Otorhinolaryngol. 2010 Nov;74(11):1273-5
references.pmid: 20846731
references.citation: J Biol Chem. 2005 Nov 4;280(44):36541-4
references.pmid: 16115897
references.citation: Future Med Chem. 2011 Jan;3(1):45-63
references.pmid: 21428825
references.citation: Ann Otol Rhinol Laryngol. 2001 Jun;110(6):574-80
references.pmid: 11407850
references.citation: Auris Nasus Larynx. 2005 Sep;32(3):243-9
references.pmid: 16040218
references.citation: Laryngoscope. 2013 Jun;123(6):1514-8
references.pmid: 23172593
references.citation: Nature. 2001 Dec 20-27;414(6866):920-4
references.pmid: 11780066