Detection and localization of interleukin-6 in the rat middle ear during experimental acute otitis media, using mRNA in situ hybridization and immunohistochemistry

Forséni, M.; Melhus, Åsa; Ryan, Allen F.; Bagger‐Sjöbäck, Dan; Hultcrantz, Malou

doi:10.1016/s0165-5876(00)00444-4

Cited by 13 publications

(2 citation statements)

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“…Despite the limitations of microarrays, our array data are largely consistent with histological data [ 49 ], qPCR data [ 50 ], Western blot [ 51 ] and immunohistochemical data [ 52 ] from other animal models of NTHi-induced OM. This supports DNA microarrays or other broad gene expression assays such as NextGen sequencing, as methods for the discovery of large numbers of relevant genes throughout the course of ME disease.…”

Section: Discussionsupporting

confidence: 76%

The transcriptome of a complete episode of acute otitis media

et al. 2015

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BackgroundOtitis media is the most common disease of childhood, and represents an important health challenge to the 10-15% of children who experience chronic/recurrent middle ear infections. The middle ear undergoes extensive modifications during otitis media, potentially involving changes in the expression of many genes. Expression profiling offers an opportunity to discover novel genes and pathways involved in this common childhood disease.The middle ears of 320 WBxB6 F1 hybrid mice were inoculated with non-typeable Haemophilus influenzae (NTHi) or PBS (sham control). Two independent samples were generated for each time point and condition, from initiation of infection to resolution. RNA was profiled on Affymetrix mouse 430 2.0 whole-genome microarrays.ResultsApproximately 8% of the sampled transcripts defined the signature of acute NTHi-induced otitis media across time. Hierarchical clustering of signal intensities revealed several temporal gene clusters. Network and pathway enrichment analysis of these clusters identified sets of genes involved in activation of the innate immune response, negative regulation of immune response, changes in epithelial and stromal cell markers, and the recruitment/function of neutrophils and macrophages. We also identified key transcriptional regulators related to events in otitis media, which likely determine the expression of these gene clusters. A list of otitis media susceptibility genes, derived from genome-wide association and candidate gene studies, was significantly enriched during the early induction phase and the middle re-modeling phase of otitis but not in the resolution phase. Our results further indicate that positive versus negative regulation of inflammatory processes occur with highly similar kinetics during otitis media, underscoring the importance of anti-inflammatory responses in controlling pathogenesis.ConclusionsThe results characterize the global gene response during otitis media and identify key signaling and transcription factor networks that control the defense of the middle ear against infection. These networks deserve further attention, as dysregulated immune defense and inflammatory responses may contribute to recurrent or chronic otitis in children.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1475-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 76%

The transcriptome of a complete episode of acute otitis media

et al. 2015

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“…It is also possible that the production of IL-6 and PGE 2 could continue for a longer time after the initial stimulus than that of other cytokines, and/or that these mediators are not eliminated at the same rate as the other cytokines. Thus, in a pneumococcal AOM rat model, IL-6 was observed in the middle ear tissue for at least 5 days after initiation of the infection, whereas its production ceased within 24 h [23], suggesting slow elimination of this cytokine.…”

Section: Discussionmentioning

confidence: 94%

High cytokine levels in perforated acute otitis media exudates containing live bacteria

Skovbjerg

Roos²,

Nowrouzian

et al. 2010

Clinical Microbiology and Infection

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Acute otitis media (AOM) is an inflammatory response to microbes in the middle ear, sometimes associated with rupture of the tympanic membrane. Human leukocytes produce different patterns of inflammatory mediators in vitro when stimulated with Gram-positive and Gram-negative bacteria, respectively. Here, we investigated the cytokine and prostaglandin E2 (PGE2) responses in middle ear fluids (MEFs) from children with spontaneously perforated AOM, and related the mediator levels to the presence of pathogens detected by culture (live) or PCR (live or dead). Furthermore, the in vivo cytokine pattern was compared with that induced in leukocytes stimulated by dead bacteria in vitro. MEFs with culturable pathogenic bacteria contained more interleukin (IL)-1β (median: 110 μg/L vs. <7.5 μg/L), tumour necrosis factor (TNF) (6.3 μg/L vs. <2.5 μg/L), IL-8 (410 μg/L vs. 38 μg/L) and IL-10 (0.48 μg/L vs. <0.30 μg/L) than culture-negative fluids, irrespective of PCR findings. IL-6 and PGE2 were equally abundant (69-110 μg/L) in effusions with live, dead or undetectable bacteria. Cytokine levels were unrelated to bacterial species and to the presence or absence of virus. Similar levels of TNF and IL-6 as found in the MEFs were obtained by in vitro stimulation of leukocytes, whereas 11 times more IL-1β and 3.5 times more IL-8 were produced in vivo, and 22 times more IL-10 was produced in vitro. Vigorous production of proinflammatory cytokines accompanies AOM with membrane rupture, regardless of the causative agent, but the production seems to cease rapidly once the bacteria are killed and fragmented. IL-6 and PGE2, however, remain after bacterial disintegration, and may play a role in the resolution phase.

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