Abstract
Galectins have been implicated in T cell homeostasis playing complementary pro-apoptotic roles. Here we show that galectin-8 (Gal-8) is a potent pro-apoptotic agent in Jurkat T cells inducing a complex phospholipase D/phosphatidic acid signaling pathway that has not been reported for any galectin before. Gal-8 increases phosphatidic signaling, which enhances the activity of both ERK1/2 and type 4 phosphodiesterases (PDE4), with a subsequent decrease in basal protein kinase A activity. Strikingly, rolipram inhibition of PDE4 decreases ERK1/2 activity. Thus Gal-8-induced PDE4 activation releases a negative influence of cAMP/protein kinase A on ERK1/2. The resulting strong ERK1/2 activation leads to expression of the death factor Fas ligand and caspase-mediated apoptosis. Several conditions that decrease ERK1/2 activity also decrease apoptosis, such as anti-Fas ligand blocking antibodies. In addition, experiments with freshly isolated human peripheral blood mononuclear cells, previously stimulated with anti-CD3 and anti-CD28, show that Gal-8 is pro-apoptotic on activated T cells, most likely on a subpopulation of them. Anti-Gal-8 autoantibodies from patients with systemic lupus erythematosus block the apoptotic effect of Gal-8. These results implicate Gal-8 as a novel T cell suppressive factor, which can be counterbalanced by function-blocking autoantibodies in autoimmunity.
Highlights
Glycan-binding proteins of the galectin family have been increasingly studied as regulators of the immune response and potential therapeutic agents for autoimmune disorders [1]
Gal-8 Induces Apoptosis in Jurkat T Cells—Our previous report in Jurkat cells showed that early effects of Gal-8 used as matrix included extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent cell adhesion and asymmetric spreading within 5–30 min [10]
Jurkat cells spread on a Gal-8 matrix showed clear signs of apoptosis, such as nuclear condensation and caspase-3 activation (Fig. 1A), which we used for quantification (Fig. 1B)
Summary
Gal-8, galectin-8; DAG, diacylglycerol; ERK, extracellular signal regulated kinase; FasL, Fas ligand; IL-2, interleukin-2; PA, phosphatidic acid; PAP, phosphadic acid phosphohydrolase; PLD, phospholipase D; PKA, protein kinase A; PBMC, peripheral blood mononuclear cells; PDE, phosphodiesterase; SLE, systemic lupus erythematosus; TDG, thiodigalactoside; GST, glutathione S-transferase; MEK, mitogen-activated protein kinase/ERK kinase; RT, reverse transcription. During T cell activation, ERK1/2 contributes to enhance the expression of interleukin-2 (IL-2) required for T cell clonal expansion [29] It supports T cell survival against pro-apoptotic Fas ligand (FasL) produced by themselves and by other previously activated T cells [30, 31]. In activation-induced cell death, ERK1/2 signaling contributes to enhance the expression of FasL and its receptor Fas/CD95 [32, 33], which constitute a preponderant pro-apoptotic system in T cells [34]. Our results for the first time show that a galectin increases the PA levels, down-regulates the cAMP/PKA system by enhancing rolipram-sensitive PDE activity, and induces an ERK1/2-dependent expression of the pro-apoptotic factor FasL. The pro-apoptotic function of Gal-8 seems to be unique in its susceptibility to inhibition by antiGal-8 autoantibodies
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