Blockage by SP600125 of Fcepsilon receptor-induced degranulation and cytokine gene expression in mast cells is mediated through inhibition of phosphatidylinositol 3-kinase signalling pathway.
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 (FcepsilonRI)-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 FcepsilonRI-induced JNK activation did not correlate with that of serotonin release. Furthermore, FcepsilonRI-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 FcepsilonRI-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 (p110delta) of PI3K. Thus, SP600125 exerts its influence on mast cell functions by inhibiting the kinase activity of PI3K, but not JNK.
Tanemura
Shuhei
S
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
Momose
Haruka
H
Shimizu
Nao
N
Kitagawa
Daiju
D
Seo
Jungwon
J
Yamasaki
Tokiwa
T
Nakagawa
Kentaro
K
Kajiho
Hiroaki
H
Penninger
Josef M
JM
Katada
Toshiaki
T
Nishina
Hiroshi
H
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020013:Calcium Signaling / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000172:deficiency / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism
D000873:Anthracenes; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017455:Receptors, IgE; D018047:Receptors, Purinergic P1; C432165:pyrazolanthrone; D058534:Class I Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human