Galectin-8 Induces Apoptosis in Jurkat T Cells by Phosphatidic Acid-mediated ERK1/2 Activation Supported by Protein Kinase A Down-regulation

Norambuena A.; Metz, C; Vicuña L.; Silva, A; Pardo E.; Oyanadel, C; Massardo, L; González A; Soza A.

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. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Más información

Título según WOS: Galectin-8 Induces Apoptosis in Jurkat T Cells by Phosphatidic Acid-mediated ERK1/2 Activation Supported by Protein Kinase A Down-regulation
Título según SCOPUS: Galectin-8 induces apoptosis in Jurkat T cells by phosphatidic acid-mediated ERK1/2 activation supported byprotein kinase A down-regulation
Título de la Revista: JOURNAL OF BIOLOGICAL CHEMISTRY
Volumen: 284
Número: 19
Editorial: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Fecha de publicación: 2009
Página de inicio: 12670
Página final: 12679
Idioma: English
URL: http://www.jbc.org/cgi/doi/10.1074/jbc.M808949200
DOI:

10.1074/jbc.M808949200

Notas: ISI, SCOPUS