Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigates the effects of adenosine and its analogues on Cl- secretion in primary cultures of gerbil middle ear epithelium. Short-circuit current (Isc), an index of transepithelial active transport, was measured on the same cells cultured on porous filters. Baseline Isc and transepithelial resistance were 27.0 +/- 0.7 microA cm-2 and 275 +/- 7 omega cm2, respectively (n = 178). Extracellular adenosine and its analogues elicited a sustained increase in Isc when added to apical or basolateral surfaces. Both the A2A selective agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine and the A2A/A2B nonselective agonist 5'-(N-ethyl-carboxamido)adenosine (NECA) increased Isc, but NECA was more effective than CGS21680. A1 selective antagonist 8-cyclopentyl-1,3-dipropylxanthine did not reduce NECA-induced Isc. These results suggest the presence of both A2A and A2B receptors. NECA did not stimulate a rise in the intracellular Ca2+ concentration ([Ca2+]i) in single middle ear epithelial cells cultured on glass coverslips. Dibutyryl cAMP (dbcAMP) induced an initial transient increase in Isc followed by the sustained plateau. Addition of dbcAMP also caused a transient increase in [Ca2+]i. The protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, greatly reduced the increase in the Isc responses to NECA. 1,2-Bis-(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid-acetoxymethyl ester influenced neither the NECA-induced increase in Isc nor the dbcAMP-induced sustained phase of Isc, but greatly inhibited the dbcAMP-induced transient increase in Isc. Glibenclamide, a cystic fibrosis transmembrane conductance regulator (CFTR) channel inhibitor, reduced the NECA-induced Isc. These results indicate that extracellular adenosine and its analogues activate the cAMP-protein kinase A system, but not intracellular Ca(2+)-dependent mechanisms, leading to Cl- secretion, possibly through the CFTR Cl- channels in the cultured gerbil middle ear epithelium.
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PMID:A2 adenosine receptors in Mongolian gerbil middle ear epithelium and their regulation of Cl- secretion. 964 28

Mucosal hyperplasia is a characteristic component of otitis media. The present study investigated the participation of signaling via the Jun N-terminal protein kinase (JNK) mitogen-activated protein kinase in middle ear mucosal hyperplasia in animal models of bacterial otitis media. Otitis media was induced by the inoculation of nontypeable Haemophilus influenzae into the middle ear cavity. Western blotting revealed that phosphorylation of JNK isoforms in the middle ear mucosa preceded but paralleled mucosal hyperplasia in this in vivo rat model. Nuclear JNK phosphorylation was observed in many cells of both the mucosal epithelium and stroma by immunohistochemistry. In an in vitro model of primary rat middle ear mucosal explants, bacterially induced mucosal growth was blocked by the Rac/Cdc42 inhibitor Clostridium difficile toxin B, the mixed-lineage kinase inhibitor CEP11004, and the JNK inhibitor SP600125. Finally, the JNK inhibitor SP600125 significantly inhibited mucosal hyperplasia during in vivo bacterial otitis media in guinea pigs. Inhibition of JNK in vivo resulted in a diminished proliferative response, as shown by a local decrease in proliferating cell nuclear antigen protein expression by immunohistochemistry. We conclude that activation of JNK is a critical pathway for bacterially induced mucosal hyperplasia during otitis media, influencing tissue proliferation.
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PMID:Jun N-terminal protein kinase enhances middle ear mucosal proliferation during bacterial otitis media. 1732 51

Human epithelial mucin, the major glycoprotein component of mucus, plays a critical role in host innate defense response against invading microbes by facilitating the mucociliary clearance. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in not only defective mucosal defense but also conductive hearing loss in the middle ear and mucus obstruction in the airway. Indeed, mucus overproduction is a hall-mark of otitis media (OM) and chronic obstructive pulmonary diseases (COPD). Thus, tight regulation of mucin production plays an important role in maintaining an appropriate balance between beneficial and detrimental outcomes. We previously reported that Streptococcus pneumoniae (S. pneumoniae) up-regulates MUC5AC mucin expression via a positive MAPK ERK1/2 and a negative JNK1/2 signaling pathway. However, the signaling components including the up-stream activators and the down-stream transcription factors involved in these two path-ways remain largely unknown. In the present study, we showed that positive regulation of MUC5AC mucin expression by ERK1/2 is dependent on Ras-Raf-1 signaling pathway, whereas the negative regulation of MUC5AC expression by JNK1/2 is dependent on MEKK3. Moreover, transcriptional factor AP-1 acts as a key regulator for both of the positive and negative regulation of MUC5AC mucin expression as evidenced by mutagenesis analysis of two AP-1 sites in the promoter region of human MUC5AC mucin gene. Ras-Raf1-ERK1/2-dependent AP-1 activation positively regulates MUC5AC mucin induction by S. pneumoniae, whereas MEKK3-JNK1/2-dependent AP-1 activation negatively regulates it. Therefore, our data unveiled a novel signaling mechanism underlying the tight regulation of MUC5AC mucin induction by S. pneumoniae and may lead to the development of new therapeutic strategy for reducing mucus overproduction in both OM and COPD.
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PMID:Differential regulation of Streptococcus pneumoniae-induced human MUC5AC mucin expression through distinct MAPK pathways. 1995 40

Otitis media (OM) is the most common childhood bacterial infection and the major cause of conductive hearing loss in children. Mucus overproduction is a hallmark of OM. Streptococcus pneumoniae is the most common gram-positive bacterial pathogen causing OM. Among many mucin genes, MUC5AC has been found to be greatly up-regulated in the middle ear mucosa of human patients with OM. We previously reported that S. pneumoniae up-regulates MUC5AC expression in a MAPK ERK-dependent manner. We also found that MAPK phosphatase-1 (MKP-1) negatively regulates S. pneumoniae-induced ERK-dependent MUC5AC up-regulation. Therapeutic strategies for up-regulating the expression of negative regulators such as MKP-1 may have significant therapeutic potential for treating mucus overproduction in OM. However, the underlying molecular mechanism by which MKP-1 expression is negatively regulated during S. pneumoniae infection is unknown. In this study we show that phosphodiesterase 4B (PDE4B) mediates S. pneumoniae-induced MUC5AC up-regulation by inhibiting the expression of a negative regulator MKP-1, which in turn leads to enhanced MAPK ERK activation and subsequent up-regulation of MUC5AC. PDE4B inhibits MKP-1 expression in a cAMP-PKA-dependent manner. PDE4-specific inhibitor rolipram inhibits S. pneumoniae-induced MUC5AC up-regulation both in vitro and in vivo. Moreover, we show that PDE4B plays a critical role in MUC5AC induction. Finally, topical and post-infection administration of rolipram into the middle ear potently inhibited S. pneumoniae-induced MUC5AC up-regulation. Collectively, these data demonstrate that PDE4B mediates ERK-dependent up-regulation of mucin MUC5AC by S. pneumoniae by inhibiting cAMP-PKA-dependent MKP-1 pathway. This study may lead to novel therapeutic strategy for inhibiting mucus overproduction.
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PMID:Phosphodiesterase 4B mediates extracellular signal-regulated kinase-dependent up-regulation of mucin MUC5AC protein by Streptococcus pneumoniae by inhibiting cAMP-protein kinase A-dependent MKP-1 phosphatase pathway. 2261 99

Otitis media is a common disease in childhood. In adults, the disease is relatively rare, but more frequently associated with complications. Possible reasons for this discrepancy are age-related differences in pathogen exposure, anatomy of the Eustachian tube and immune system. The objective of this study was to analyze the relationship between age and the mucosal immune system in the middle ear. It is hypothesized that genes involved in the middle ear immune system will change with age. A comprehensive assessment of these genetic differences using the techniques of complementary DNA has not been performed. Complementary DNA microarray technology was used to identify immune-related genes differentially expressed between the normal middle ear mucosa of young (10 days old) and adult rats (80 days old). Data were analyzed using tools of bioinformatics. A total of 260 age-related genes were identified, of which 51 genes were involved in the middle ear mucosal immune system. Genes related to the innate immune system, including alpha-defensin, calcium-binding proteins S100A9 and S100A8, were upregulated in young rats, whereas genes related to the adaptive immune system, including CD3 molecules, zeta-chain T-cell receptor-associated protein kinase and linker of activated T-cells, were upregulated in the adult. This study concludes that the normal middle ear immune system changes with age. Genes related to the innate immune system are upregulated in young rats, whereas genes related to the adaptive immune system are upregulated in adults.
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PMID:The middle ear immune defense changes with age. 2556 39