Phosphatase inhibition potentiates IL-6 production by mast cells in response to FcepsilonRI-mediated activation: involvement of p38 MAPK.
Mast cells are crucial effector cells in the immune response through mediator secretion and release of cytokines. A coordinated balance between protein kinases and phosphatases plays an essential role in the regulation of mast cell mediator secretion. We have previously shown that treatment of mast cells with okadaic acid (OA), a protein phosphatase 2A (PP2A) inhibitor, results in a dose-dependent increase in interleukin (IL)-6 production. We show here for the first time a synergism between OA and immunoglobulin E (IgE)-mediated IL-6 secretion by murine bone marrow-derived mast cells (BMMC). Selective p38 mitogen-activated protein kinase (p38 MAPK) inhibition reduces OA and IgE-mediated IL-6 production. Regulation of p38 MAPK by PP2A was demonstrated, as OA treatment caused a dose-dependent increase in p38 MAPK phosphorylation. Antigen-mediated activation of murine mast cells also resulted in an increase in p38 MAPK phosphorylation, which was potentiated by cotreatment of the cells with OA. Lastly, in two mast cell lines (human mast cell-1 5C6 and murine MC/9) and primary-cultured murine BMMC, we show by coimmunoprecipitation an interaction between p38 MAPK and PP2A. These data support a role for PP2A through interaction with p38 MAPK in the regulation of IgE-dependent mast cell activation.
Department of Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Robert T M
RT
Boudreau
David W
DW
Hoskin
Tong-Jun
TJ
Lin
D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2; D017455:Receptors, IgE / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D017455:Receptors, IgE; D019319:Okadaic Acid; D007073:Immunoglobulin E; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2