Cytokines, Immunoglobulins, and Bacterial Pathogens in Middle Ear Effusions

Yellon, Robert F.; Doyle, William J.; Whiteside, Theresa L.; Diven, Warren F.; March, Antonio Riera; Fireman, Philip

doi:10.1001/archotol.1995.01890080033006

Cited by 92 publications

(99 citation statements)

References 16 publications

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“…These mucins vary in size and can be membrane bound or secreted. The process of defining the specific functions of each of these mucin products in the middle ear is still ongoing.There is currently a growing body of evidence demonstrating that a cytokine mediated inflammatory response is important in the pathophysiology of acute and chronic otitis media [8][9][10][11][12][13][14][15]. This study, along with similar studies conducted in our laboratory using chinchilla middle ear epithelial cells, shows clear evidence of this cytokine mediated inflammatory response particularly as it relates to mucin pathophysiology and regulation.…”

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confidence: 54%

“…Several cytokines have been found in a high percentage of these effusions, including TNF-α and IL -1β [6]. In addition to the general inflammatory regulatory mechanisms associated with these cytokines evidence exists that TNF-α and IL-1β are also integral in the inflammatory response in otitis media and regulate mucin production and secretion from middle ear epithelium [7][8][9][10][11]. Previous investigations in our laboratory using primary culture chinchilla middle ear epithelial (CMEE) cells have laid the ground work for the current investigations [12].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

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Cytokine regulation of mucin secretion in a human middle ear epithelial model

2008

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Objectives-Middle ear mucins are associated with otitis media (OM), contribute to hearing loss and are regulated by cytokines. This work investigates the regulation of mucin secretion from human middle ear epithelial cells (HMEEC) by inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and cytokine inhibitors interleukin-1 receptor antagonist (IL-1ra) and antitumor necrosis factor-α antibody (TNFab).Methods-HMEEC were exposed to IL-1β and TNF-α in a dose-and time-dependent manner. Cytokine stimulated HMEEC were also exposed to IL-1ra and TNFab in a dose-dependent manner. Mucin secretion was characterized by exclusion chromatography and liquid scintillation.Results-HMEEC exposed to IL-1β and TNF-α demonstrated significant upregulation of mucin secretion in a dose-dependent fashion. Cultures exposed to IL-1β at 100ng/ml and TNF-α at 200ng/ ml showed increased mucin secretion in time-dependent experiments at 16 hours (P=0.00008) for TNF-α and 8 (P=0.028) and 16 hours (P=0.00001) for IL-1 β. IL-1ra and TNFab inhibited the effects of increased mucin secretion by IL-1β and TNF-α. Conclusions-IL-1βand TNF-α upregulate mucin secretion from HMEEC in a dose-and timedependant manner and these effects can be inhibited by cytokine blockade. Improved understanding of these mechanisms has the potential to alter the approach and management of OM and lead to novel therapeutic interventions.Keywords otitis media; mucin; interleukin-1 β; tumor necrosis factor -α IntroductionOtitis media (OM) is the most common diagnosis in children who visit physicians for illness in the United States [1]. Along with this disease prevalence is an economic burden of treatment in the billions of dollars per year in the US [2]. A more thorough understanding of the pathophysiology and the inflammatory events that occur during this disease process is needed to provide novel solutions in the treatment of OM. In particular, although antibiotic treatment has been the mainstay of otitis media treatment, the increasing prevalence of microbial resistance will make the singular use of antibiotics challenging. Additionally, evidence has Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptCytokine. Author manuscript; available in PMC 2009 January 1. Published in final edited form as:Cytokine. 2008 January ; 41(1): 38-43. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been generated suggesting that chronic inflammatory responses to middle ear pathogens may be important in the development of otitis media with effusion (OME) and rais...

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Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Cytokine regulation of mucin secretion in a human middle ear epithelial model

2008

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“…IL-8, a potent chemoattractant, is produced predominantly by monocytes, macrophages, and endothelial cells in response to stimuli such as lipopolysaccharide and TNF-␣ (2). Numerous cytokines and growth factors have been detected in middle ear fluid of children with otitis media (9,14). In a previous study (8), serum IL-6 levels were positively correlated with bacterial AOM, especially when caused by S. pneumoniae.…”

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confidence: 89%

“…Interleukin-1␤ (IL-1␤) is known to induce synthesis of tumor necrosis factor alpha (TNF-␣) (14) and the growth of osteoclasts and fibroblasts and to cause hemodynamic changes and fever. IL-6 is a potent inducer of C-reactive protein and has been shown in vitro and in animal models to inhibit TNF-␣ (1).…”

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Systemic Inflammatory Responses in Children with Acute Otitis Media Due toStreptococcus pneumoniaeand the Impact of Treatment with Clarithromycin

Scharer

Zaldivar

González

et al. 2003

Clin Vaccine Immunol

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This pilot study was designed to determine the serum cytokine profile of acute otitis media (AOM) due to Streptococcus pneumoniae and the impact of clarithromycin (Abbott Laboratories, Inc). Serum levels of interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), IL-6, and IL-8 were measured at diagnosis and 3 to 5 days after start of antibiotic treatment in 10 patients (mean age, 18.3 ؎ 13.9 months) who had middle ear fluid culture positive for S. pneumoniae. The mean concentrations of all cytokines were elevated at diagnosis of AOM compared to levels in healthy controls, yet only IL-6 reached statistical significance (P ‫؍‬ 0.05). IL-6 showed a statistically significant decrease in mean serum concentration at visit 2 (P ‫؍‬ 0.03). IL-8 displayed a similar pattern to IL-6, but the difference between samples from day 1 and day 2 did not reach statistical significance. The cytokines IL-1␤ and TNF-␣ appear to be elevated in the serum of patients with S. pneumoniae AOM, but there was no significant change between mean serum levels obtained pre-and postinitiation of antibiotic treatment in the time frame studied. The results suggest a systemic inflammatory response as evidenced by increased IL-6. A significant decrease of IL-6 and improvement of clinical symptoms were observed. Determining cytokine levels, especially IL-6, in AOM could offer a powerful tool for objective assessment of response to treatment, minimizing unnecessary treatment of asymptomatic children who may still have some otoscopic findings suggestive of AOM at follow-up visits.

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“…In vitro studies showed that IgA downregulates TNF-␣ release in human monocytes (43,45). Yellon et al (49) assayed MEEs from children with OM and did not find any significant correlation between the concentrations of inflammatory cytokines and immunoglobulins. We showed that inflammatory-cytokine release was tempered after intranasal immunization and that concentrations of TNF-␣ were significantly lower (P ϭ 0.041) in MEEs of P6ϩCT-immunized mice EFFECT OF NASAL VACCINE ON EXPERIMENTAL OTITIS MEDIAthan those in control mice on postchallenge day 3.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Immunization Enhances Clearance of NontypeableHaemophilus influenzaeand Reduces Stimulation of Tumor Necrosis Factor Alpha Production in the Murine Model of Otitis Media

et al. 2001

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Nontypeable Haemophilus influenzae (NTHi) is a major pathogen causing otitis media (OM). One of the outer membrane proteins of NTHi, P6, is a common antigen to all strains and is considered a candidate for mucosal vaccine. We have previously reported that intranasal immunization with P6 and cholera toxin (CT) could induce P6-specific immunoglobulin A (IgA) antibodies in the middle ear. In the present study, we assessed the effect of intranasal immunization for the protection against NTHi-induced OM. Mice were immunized intranasally with P6 and CT as an adjuvant on days 0, 7, and 14. Control mice were given phosphate-buffered saline (PBS) without antigen. One week after the final immunization, a suspension of live NTHi (10 7 CFU) was injected into the tympanic cavity to induce experimental OM. On days 3 and 7 after bacterial challenge, mice were killed and middle ear effusions (MEEs) were collected. All immunized mice showed elevated titers of P6-specific antibodies in MEEs. The rank order of specific antibody included, from highest to lowest levels, IgG, IgA, and IgM. In addition, immunized mice showed enhanced clearance of NTHi from the middle ear and the number of NTHi in MEEs of immunized mice was reduced by 97% on day 3 and by 92% on day 7 after bacterial challenge relative the number in the MEEs of control mice. The protective effect of intranasal immunization on the incidence of NTHi-induced experimental OM was evident on day 7 after challenge. By day 7, the number of MEEs in immunized mice was 64% less than that in control mice and the incidence of NTHi culture-positive MEEs in immunized mice was 56% less than that in control mice. Less stimulation of tumor necrosis factor alpha (TNF-␣) production in the middle ear was evident on day 3 after challenge. Immunized mice showed lower concentrations of TNF-␣ in MEEs. These results indicate that intranasal immunization affords protection against experimental OM as evidenced by enhanced clearance of NTHi and less stimulation of TNF-␣ production in the middle ear. These findings suggest that a nasal vaccine might be useful for preventing OM.Otitis media (OM) is one of the most common infectious diseases in children, and the peak incidence of this disease occurs in early childhood. Nontypeable Haemophilus influenzae (NTHi) is a major causative pathogen of OM and is often isolated from middle ear effusions (MEEs) and the nasopharynx (12). Because of the increased incidence of antibioticresistant strains of NTHi in recent years, the development of a vaccine against this bacterium is considered an important goal for public health (14, 15). Recent efforts to develop an effective vaccine candidate against NTHi have focused on P6, an outer membrane protein of NTHi and a common antigen to all strains (32, 33).The middle ear mucosa is capable of producing local and systemic responses after an appropriate antigenic stimulus (30). Local immunity in the middle ear, in conjunction with systemic immunity, plays an important role in OM. Antigenspecific antibodies appear in MEE ...

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Cytokines, Immunoglobulins, and Bacterial Pathogens in Middle Ear Effusions

Cited by 92 publications

References 16 publications

Cytokine regulation of mucin secretion in a human middle ear epithelial model

Cytokine regulation of mucin secretion in a human middle ear epithelial model

Systemic Inflammatory Responses in Children with Acute Otitis Media Due toStreptococcus pneumoniaeand the Impact of Treatment with Clarithromycin

Intranasal Immunization Enhances Clearance of NontypeableHaemophilus influenzaeand Reduces Stimulation of Tumor Necrosis Factor Alpha Production in the Murine Model of Otitis Media

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