Expression of Cytokine Genes during Pneumococcal and NontypeableHaemophilus influenzaeAcute Otitis Media in the Rat

Abstract

Acute otitis media (AOM) elicits potent inflammatory responses from the cells of the middle ear mucosa as well as from infiltrating leukocytes. To explore host responses during experimental AOM induced by Streptococcus pneumoniae type 3 and nontypeable Haemophilus influenzae (NTHi), otomicroscopy findings and expression of cytokine genes in the middle ear were monitored up to 1 month postinoculation. The mucosa and infiltrating cells responded rapidly to the bacterial challenge. Otomicroscopically, AOM appeared 1 day after NTHi inoculation and 3 days after pneumococcus inoculation. Pneumococcal AOM was more severe than NTHi otitis, but in general, lower transcript levels were detected in pneumococcus-infected than in NTHi-infected animals. Interleukin-6 (IL-6) mRNA levels peaked at 3 to 6 h for both pneumococcus-infected and NTHiinfected animals. IL-1␣, tumor necrosis factor alpha, and IL-10 mRNA levels peaked at 6 h for NTHi otitis and 1 to 3 days for pneumococcal otitis. Comparing otomicroscopy with expression profiles, it would appear that the majority of cytokine mRNAs had passed their peak before the AOM diagnosis could be made clinically. Only transforming growth factor ␤ mRNA followed a slower time course, peaking very late and continuing expression even after the AOM was otomicroscopically resolved. IL-2 and IL-4 mRNAs were not detected in any animal at any time. Most of the investigated cytokines are very early markers for AOM and may be involved in initiation of inflammation, but they would be poor targets for pharmacological manipulation since their levels decline before clinical signs appear.

Synergistic activation of NF-κB by nontypeable Haemophilus influenzae and tumor necrosis factor α

“…In review of the current studies on NF-B regulation in bacterial infections, most studies have fully focused on investigating how NF-B is activated by a single inducer at a time (8)(9)(10)(11). Although these studies are indeed critical for our understanding of the molecular basis underlying bacteria-induced inflammation, the information derived from these studies may be insufficient for fully understanding how NF-B is induced in vivo where both exogenous and endogenous mediators are present simultaneously.…”

“…In children, it causes otitis media (OM), which is the most common childhood infection and the leading cause of conductive hearing loss (2,3), whereas in adults, it exacerbates chronic obstructive pulmonary disease (COPD), which is the fourth leading cause of death in the United States (4,5). Like most bacterial infections, both OM and COPD are characterized also by inflammation, which is mediated mainly by inflammatory cytokines and chemokines, such as tumor necrosis factor ␣ (TNF-␣), IL-1␤, and IL-8 (6)(7)(8). Among a variety of transcription regulators, NF-B has been shown to play a critical role in regulating the expression of many genes encoding cytokines, chemokines, and other mediators involved in inflammatory responses (9).…”

Genetic Polymorphisms in Immunoresponse GenesTNFA,IL6,IL10, andTLR4Are Associated With Recurrent Acute Otitis Media

“…Increased expression of TNF-␣, IL-1␤, IL-6, and IL-10 was observed during experimental otitis media in animals. 3,4 Therefore, in a common disease such as otitis media, genetic variations may lead to altered inflammatory responses and an otitis-prone condition. For instance, bacterial endotoxin is recognized by several Toll-like receptors (TLRs), which in turn stimulate TNF-␣ production, thus affecting numerous other pathways such as cytokine production, immunoglobulin responses, and mucin production.…”

Expression of Cytokine and Chemokine Genes by Human Middle Ear Epithelial Cells Induced by Influenza A Virus andStreptococcus pneumoniaeOpacity Variants

“…Innate proinflammatory responses induced in host cells by S. pneumoniae infection that may contribute to the OM pathology include the synthesis and release of cytokines, chemokines, and other inflammatory mediators. Extensive evidence suggests that the middle ear epithelium not only is a physical barrier but also has the potential to synthesize a variety of cytokines, including interleukin-1 (IL-1), IL-6, IL-8, and IL-10, which are recognized as being important local mediators in acute inflammation in various animal models of OM (20,28,33). Activation of host epithelial and endothelial cells by cytokines results in a shift in S. pneumoniae adherence to new receptors, particularly the platelet-activating factor receptor (10).…”