c-jun controls the ability of IL-12 to induce IL-10 production from human memory CD4+ T cells.
IL-12p70 is an immunoregulatory cytokine that has been shown to induce IL-10 production from CD4+ T cells, yet the underlying cellular mechanisms controlling this process are poorly understood. In the present study, we demonstrate that IL-12p70 induces IL-10 production from human memory CD4+ T cells via a PI3K-dependent signaling mechanism. Specifically, stimulation of human memory CD4+ T cells in the presence of IL-12p70 lead to increased PI3K activity and the subsequent phosphorylation and inactivation of the downstream constitutively active serine/threonine kinase, glycogen synthase kinase-3beta (GSK3beta). Inhibition of PI3K prevented the inactivation of GSK3beta by IL-12p70, as well as the subsequent ability of IL-12p70 to augment IL-10 levels by memory CD4+ T cells. Moreover, ectopic expression of a constitutively active form of GSK3beta abrogated the ability of IL-12p70 to increase IL-10 production by TCR-stimulated CD4+ T cells. In contrast, direct inhibition of GSK3 mimicked the effect of IL-12p70 on IL-10 production by memory CD4+ T cells. Analysis of downstream transcription factors identified that the ability of IL-12p70 to inactivate GSK3beta lead to increased levels of c-jun. The ability of IL-12p70 to inactivate GSK3beta and induce c-jun levels was required for IL-12 to augment IL-10 production by human memory CD4+ T cells, since small interfering RNA-mediated gene silencing of c-jun abrogated this process. These studies identify the cellular mechanism by which IL-12 induces IL-10 production from human memory CD4+ T cells.
Garcia
Carlos A
CA
Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Wang
Huizhi
H
Benakanakere
Manjunatha R
MR
Barrett
Elyse
E
Kinane
Denis F
DF
Martin
Michael
M
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
C508609:IL10 protein, human; D016755:Proto-Oncogene Proteins c-jun; D016753:Interleukin-10; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3