Evidence for a role of phosphatidylinositol 3-kinase in IL-4-induced germline C epsilon transcription.
Association of interleukin-4 receptor (IL-4R) with phosphatidylinositol 3-kinase (PI3-kinase) has been demonstrated as the proximal event of IL-4 signaling. We investigated the role of this enzyme in the IL-4 signaling pathway in a human Burkitt lymphoma B cell line, DND39, that expresses germline C epsilon transcripts in response to IL-4. Stimulation of DND39 cells with IL-4 resulted in an accumulation of PI-3-monophosphate as well as a decrease of PI-4,5-bisphosphate, which were abrogated by wortmannin, a potent inhibitor of PI3-kinase. Activation of PI3-kinase was further confirmed by the finding that IL-4 caused an increase in PI3-kinase activity coimmunoprecipitated with anti-IL-4R and with anti-JAK3 kinase antibodies. As a possible downstream event of PI3-kinase activation, the translocation of a zeta isoform of protein kinase C (PKC) from the cytosol to the membrane fraction was observed after IL-4 stimulation, and wortmannin also suppressed this translocation. Moreover, IL-4-induced expression of germline C epsilon transcription was inhibited not only by wortmannin, but also by a PKC inhibitor, K252a. These results suggest that the signaling pathway involving PI3-kinase and PKC zeta plays an important role in induction of germline C epsilon transcription in DND39 cells by IL-4.
Ikizawa
K
K
Clinical Research Center for Allergy, National Sagamihara Hospital, Japan.
Kajiwara
K
K
Basaki
Y
Y
Koshio
T
T
Yanagihara
Y
Y
D000595:Amino Acid Sequence; D000730:Androstadienes / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000096:biosynthesis* / Q000235:genetics; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000235:genetics; D026121:Indole Alkaloids; D015847:Interleukin-4 / Q000502:physiology*; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000032:analysis / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007127:Immunoglobulin Constant Regions; D026121:Indole Alkaloids; D012333:RNA, Messenger; D015847:Interleukin-4; D007073:Immunoglobulin E; C049985:staurosporine aglycone; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D000077191:Wortmannin