Ganglioside control over IL-4 priming and cytokine production in activated T cells.
Our previous studies have shown that the enzymatic activities of Neu-1, an endogenous sialidase encoded in the murine MHC, are involved in promoting IL-4 synthesis by naive CD4(+)T cells. Our present studies have characterized responsible sialoconjugate targets of Neu-1 and questioned possible biochemical mechanisms responsible for their regulatory influences on IL-4 gene expression. These studies determined that treatment of T cells with the naturally occurring ganglioside GM3 inhibited the production of IL-4 without affecting the production of IL-2. An analysis of IL-4-primed CD4(+)T cells further demonstrated that GM3 treatment specifically inhibited the restimulated production of IL-4, IL-5 and IL-13, without inhibiting the production of IL-2 and IFN-gamma. The inhibitory effects of GM3 could be overcome by treatment with thapsigargin or ionomycin, suggesting ganglioside regulation occurs upstream of activation-induced calcium mobilization. GM3 treatment attenuated the level of calcium influx following CD3epsilon crosslinking, and CD4(+)T cells from Neu-1-deficient B10.SM strain mice (neu-1(a)and IL-4-deficient) expressed reduced levels of intracellular calcium following activation. Our results indicate that activities by membrane gangliosides can influence the cytokine programs in CD4(+)T cells, possibly through the modulation of calcium responses induced by T cell activation.
Chen
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Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Ding
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Daynes
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005677:G(M1) Ganglioside / Q000378:metabolism* / Q000494:pharmacology; D005679:G(M3) Ganglioside / Q000378:metabolism* / Q000494:pharmacology; D018793:Interleukin-13 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis*; D015848:Interleukin-5 / Q000096:biosynthesis*; D007424:Intracellular Fluid / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D009439:Neuraminidase / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D005679:G(M3) Ganglioside; D018793:Interleukin-13; D015848:Interleukin-5; D007476:Ionophores; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015847:Interleukin-4; D005677:G(M1) Ganglioside; D015759:Ionomycin; C110128:Neu1 protein, mouse; D009439:Neuraminidase; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium