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Journal of Biochemistry Advance Access originally published online on December 23, 2008
Journal of Biochemistry 2009 145(3):345-354; doi:10.1093/jb/mvn172
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© The Authors 2008. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

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

Shuhei Tanemura1,2, Haruka Momose1,2,3, Nao Shimizu1,2, Daiju Kitagawa1,2, Jungwon Seo1,2, Tokiwa Yamasaki1,2, Kentaro Nakagawa1,2, Hiroaki Kajiho2, Josef M. Penninger4, Toshiaki Katada2 and Hiroshi Nishina1,*

1Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510; 2Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033; 3Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo 208-0011, Japan; and 4IMBA: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, Vienna A-1030, Austria

*To whom correspondence should be addressed. Tel: +81-3-5803-4659; Fax: +81-3-5803-5829; E-mail: nishina.dbio{at}mri.tmd.ac.jp

Received November 25, 2008; Accepted December 5, 2008


  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 (Fc{varepsilon}RI)-induced degranulation (serotonin release) and cytokine gene expression [interleukin (IL)-6, tumour necrosis factor-{alpha} and IL-13] in bone marrow-derived mast cells, were almost completely inhibited by SP600125. However, the time course of Fc{varepsilon}RI-induced JNK activation did not correlate with that of serotonin release. Furthermore, Fc{varepsilon}RI-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 Fc{varepsilon}RI-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 (p110{delta}) of PI3K. Thus, SP600125 exerts its influence on mast cell functions by inhibiting the kinase activity of PI3K, but not JNK.

Key Words: IgE, JNK, mast cell, PI3K, SP600125

Abbreviations: Ab, antibody; BMMC, bone-marrow derived mast cell; ERK, extracellular signal-regulated kinase; Gab2, Grb2-associated binder 2; HA, hemagglutinin; IL, interleukin; JNK, c-Jun N-terminal kinase; LPA, lysophophatidic acid; mAb, monoclonal Ab; MKK, MAPK kinase; pAb, polyclonal Ab; PIP3, phosphatidylinositol-3,4,5-triphosphate; SAPK, stress-activated protein kinase; SEK, stress-activated protein kinase/extracellular signal-regulated kinase kinase; TNF{alpha}, tumor necrosis factor {alpha}


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