Involvement of a phosphatidylinositol 3-kinase-p38 mitogen activated protein kinase pathway in antigen-induced IL-4 production in mast cells.
We studied the involvement of phosphatidylinositol 3-kinase (PI3-kinase) in the antigen-induced IL-4 production in a rat mast cell line, RBL-2H3. The stimulation of IgE-sensitized RBL-2H3 cells by the antigen resulted in increased IL-4 mRNA levels followed by increased IL-4 production. Wortmannin and LY294002, PI3-kinase inhibitors, partially reduced both the antigen-induced increases in the IL-4 mRNA levels and IL-4 production in a concentration-dependent manner. Extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK), which belong to the MAPK family, were activated by the antigen stimulation, and the activation of p38 MAPK in addition to JNK was suppressed markedly by wortmannin. The phosphorylation of endogenous activating transcription factor-2, a substrate of p38 MAPK, was also inhibited by wortmannin. The specific p38 MAPK inhibitor SB203580 partially inhibited the antigen-induced IL-4 production at mRNA levels, but the MEK-1 inhibitor PD98059 enhanced it. These findings suggest that the activation of PI3-kinase and p38 MAPK is partially responsible for the antigen-induced IL-4 production in RBL-2H3 cells.
Hirasawa
N
N
Department of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan. hirasawa@mail.pharm.tohoku.ac.jp
Sato
Y
Y
Fujita
Y
Y
Ohuchi
K
K
D051698:Activating Transcription Factor 2; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004140:Dinitrophenols; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000032:analysis / Q000096:biosynthesis*; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D012709:Serum Albumin; D014157:Transcription Factors / Q000378:metabolism; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; D000730:Androstadienes; C497107:Atf2 protein, rat; D002867:Chromones; D017362:Cyclic AMP Response Element-Binding Protein; D004140:Dinitrophenols; D005419:Flavonoids; D007093:Imidazoles; D009025:Morpholines; D011725:Pyridines; D012709:Serum Albumin; D014157:Transcription Factors; C058064:dinitrophenyl-human serum albumin conjugate; D015847:Interleukin-4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin