008 - NF-κB and the nuclear kinase MSK1 in a murine model of asthma - 05/12/08

We previously reported that NF-κB activation is essential for the overexpression of the major mast cell growth factor SCF in inflammation (Da Silva et coll., Faseb J 2003). We show here the activation of the nuclear kinase MSK1 as the key step of NF-kB activation, and the consequences in a murine asthma model.

NF-κB p65 was phosphorylated at Ser276 upon IL-1β treatment as shown by Western blotting. Chromatin immunoprecipitation experiment showed binding of NF-κB, of MSK1 and of CBP to the SCF gene κB intronic enhancer. Further on, IL-1β upregulated SCF expression and this was abolished by S276C p65 mutation, MSK1 kinase-dead mutation, anti-MSK1 siRNA transfection, or by pharmacological inhibition by the H89 kinase inhibitor compound, indicating a role for MSK1 mediated S276 p65 phosphorylation in SCF expression.

Additionally, we evaluated the effect of this kinase inhibitor, compound H89 (10 mg/kg), as compared to solvent in a murine asthma model created by sensitization and challenge of mice with ovalbumin + Al(OH)3. The eosinophilic infiltrate and the associated remodelling of the airways including mucus secretion were inhibited by 80% and 60%, respectively.

In conclusion, we therefore propose MSK1 as an interesting therapeutic target to combat mast cell-associated inflammation in particular in asthma.