Blockage by SP600125 of Fc Receptor-Induced Degranulation and Cytokine Gene Expression in Mast Cells is Mediated Through Inhibition of Phosphatidylinositol 3-Kinase Signalling Pathway

Abstract

SP600125 is used as a specific inhibitor of c-Jun N-terminal kinase (JNK). We initially aimed to examine physiological roles of JNK in mast cells that play a central role in inflammatory and immediate allergic responses. We found that Fc receptor for IgE (FcεRI)-induced degranulation (serotonin release) and cytokine gene expression [interleukin (IL)-6, tumour necrosis factor-α and IL-13] in bone marrow-derived mast cells, were almost completely inhibited by SP600125. However, the time course of FcεRI-induced JNK activation did not correlate with that of serotonin release. Furthermore, FcεRI-induced degranulation and cytokine gene expression were not impaired in a JNK activator, MKK7-deficient mast cells, in which JNK activation was lost. These results indicate that the inhibitory effects by SP600125 are not due to impaired JNK activation. Instead, we found that SP600125 markedly inhibited the FcεRI-induced activation of phosphatidylinositol 3-kinase (PI3K) and Akt, the same as a PI3K inhibitor, wortmannin. Finally, we found that SP600125 specifically inhibits delta form of p110 catalytic subunit (p110δ) of PI3K. Thus, SP600125 exerts its influence on mast cell functions by inhibiting the kinase activity of PI3K, but not JNK.