In our earlier studies, ERK activation was not well correlated temporally with ME mucosal hyperplasia in an animal model of OM since it occurred very early and very late in OM. p38 activation also occurred primarily very early in OM, with peak activation 1 to 6 h after bacterial inoculation. Moreover, even AT7867 at saturating levels of the MAPK kinase ERK inhibitor U0126 or the p38 inhibitor SB203580, mucosal growth was still observed in vitro . This suggests that other pathways are involved in regulating hyperplasia. JNK was originally identified as two protein kinases, p46 and p54, which specifically phosphorylate the transcription factor c Jun on its N terminal transactivation domain at serines 63 and 73. Molecular cloning of JNK demonstrated that it is a member of the MAPK group of signaling proteins.
Ten JNK isoforms are created by alternative splicing of mRNA transcripts derived from three genes . JNK1 and JNK2 are expressed in many cell types, while JNK3 has a more limited pattern of Raltitrexed expression and is largely restricted to neuronal cells, the heart, and the testes. In parallel with ERK1 ERK2, JNK appears to be essential for activator protein 1 gene activation induced by stress and exposure to various cytokines. The JNK signaling pathway has been implicated in a large variety of pathological conditions, including inflammatory disorders, neurodegenerative diseases, and metabolic disease. Studies of various cancer cell lines have revealed high levels of JNK activity, suggesting that JNK can mediate tissue proliferation. In addition, JNK has also been shown to influence apoptosis.
The complexity of the JNK pathway provides multiple opportunities for the design of small molecule inhibitors that might modulate signaling. JNK inhibitors have shown promise in animal models for the treatment of rheumatoid arthritis. The pharmaceutical industry is bringing JNK inhibitors into clinical trials for autoimmune, anti inflammatory, and neurodegenerative diseases. The family of Rho GTPases consists of at least 21 members in mammalian cells. Rac and Cdc42, two well characterized members of the family, are known upstream activators of JNK in various cells. The mixed lineage kinases are also often found upstream of JNK. Specific inhibitors of Rac, Cdc42, and MLKs have also been developed . For this report, we investigated the role of the JNK signaling pathway in rat MEs infected with nontypeable Haemophilus influenzae.
In order to determine whether JNK signaling is involved in ME mucosal hypertrophy, activation of JNK was evaluated in a rat in vivo model of bacterial OM. In addition, specific inhibitors of the JNK pathway were used in an in vitro rat model of bacterially induced mucosal proliferation. Finally, persistent administration of a JNK inhibitor into the ME mucosa with a mini osmotic pump was evaluated in vivo during bacterial OM in guinea pigs. MATERIALS AND METHODS In vivo assessment of JNK phosphorylation. All experiments were performed according to National Institutes of Health guidelines on the care and use of laboratory animals and were approved by the institutional committee for animal experimentation.
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