title: Divergent activities of protein kinases in IL-6-induced differentiation of a human B cell line.
abstract: Lymphokines including IL-2, IL-4, and IL-6 are involved in the induction of Ig production by activated B cells. We have investigated the role of protein kinases in IL-6-induced IgM secretion by SKW6.4 cells, an IL-6 responsive B cell line. IL-6-stimulated IgM production was inhibited by elevated intracellular cAMP induced either by the addition of dibutyryl cAMP or cholera toxin. The inhibitory effect of elevated intracellular cAMP was blocked by n-(2-(Methylamino)ethyl)-5-isoquinolinesulfonic dihydrochloride (H8), an inhibitor of protein kinase A. H8 did not affect IgM secretion induced by IL-6. In contrast, the addition of 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H7), an inhibitor of protein kinase C activity, markedly inhibited IL-6-stimulated IgM production by SKW6.4 cells. H7 and elevated intracellular cAMP inhibited IgM mRNA expression and subsequent IgM synthesis by SKW6.4 cells. SKW6.4 proliferation, as determined by [3H]thymidine incorporation, was not markedly affected by IL-6, dibutyryl cAMP, cholera toxin, H7 or H8. PMA, an activator of protein kinase C, directly stimulated significant IgM secretion by SKW6.4 cells. When added to PMA-stimulated SKW6.4 cells, IL-6 stimulated additional IgM production. This observation suggested that IL-6 could stimulate differentiation without activating protein kinase C. This was confirmed by demonstrating that IL-6 did not stimulate production of diacylglycerol, did not induce the translocation of protein kinase C from the cytosolic compartment to the plasma membrane and could induce SKW6.4 cells to produce IgM after depletion of their cellular protein kinase C by PMA. Taken together these results suggests that IL-6-stimulated IgM production requires utilization of an H7-inhibitable protein kinase that can be inhibited by a protein kinase A-dependent pathway. Despite the fact that PMA can stimulate IgM production in SKW6.4 cells, IL-6 appears to use a protein kinase pathway other than protein kinase C to induce IgM production.
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10463.
authors.forename: H
authors.initials: H
authors.lastname: Goldstein
authors.forename: D
authors.initials: D
authors.lastname: Koerholz
authors.forename: L
authors.initials: L
authors.lastname: Chesky
authors.forename: X D
authors.initials: XD
authors.lastname: Fan
authors.forename: J L
authors.initials: JL
authors.lastname: Ambrus
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D007075:Immunoglobulin M; D015850:Interleukin-6; D007546:Isoquinolines; D010879:Piperazines; D012333:RNA, Messenger; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate