Abstract
Galectin-1 (gal-1), an endogenous β-galactoside-binding protein, triggers T-cell death through several mechanisms including the death receptor and the mitochondrial apoptotic pathway. In this study we first show that gal-1 initiates the activation of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 4 (MKK4), and MKK7 as upstream JNK activators in Jurkat T cells. Inhibition of JNK activation with sphingomyelinase inhibitors (20 μM desipramine, 20 μM imipramine), with the protein kinase C-δ (PKCδ) inhibitor rottlerin (10 μM), and with the specific PKCθ pseudosubstrate inhibitor (30 μM) indicates that ceramide and phosphorylation by PKCδ and PKCθ mediate gal-1-induced JNK activation. Downstream of JNK, we observed increased phosphorylation of c-Jun, enhanced activating protein-1 (AP-1) luciferase reporter, and AP-1/DNA-binding in response to gal-1. The pivotal role of the JNK/c-Jun/AP-1 pathway for gal-1-induced apoptosis was documented by reduction of DNA fragmentation after inhibition JNK by SP600125 (20 μM) or inhibition of AP-1 activation by curcumin (2 μM). Gal-1 failed to induce AP-1 activation and DNA fragmentation in CD3-deficient Jurkat 31-13 cells. In Jurkat E6.1 cells gal-1 induced a proapoptotic signal pattern as indicated by decreased antiapoptotic Bcl-2 expression, induction of proapoptotic Bad, and increased Bcl-2 phosphorylation. The results provide evidence that the JNK/c-Jun/AP-1 pathway plays a key role for T-cell death regulation in response to gal-1 stimulation.
Highlights
Apoptosis in the immune system is a process that ensures the proper removal of autoreactive T cells during thymic development and T-cell homeostasis as well as the downregulation of peripheral immune responses against antigens
Jurkat T lymphocytes exposed to gal-1 for 6 h underwent apoptosis as indicated by DNA fragmentation (Figure 1)
In this study we could show that Jun N-terminal kinase (JNK) activation is required for apoptosis of human lymphoblastoid Jurkat T cells induced by gal-1
Summary
Apoptosis in the immune system is a process that ensures the proper removal of autoreactive T cells during thymic development and T-cell homeostasis as well as the downregulation of peripheral immune responses against antigens. Shown is a representative image of three independent experiments presented by cell-surface glycoconjugates.[12] It has been shown that gal-1 presented by extracellular matrix more effectively induces apoptosis of susceptible T cells than the soluble form.[13] Gal-1 synthesis is strongly upregulated after peptide antigen-induced activation of murine T cells and inhibits antigen-induced proliferation of activated T cells.[14] These data strongly suggest a potential autocrine suicide mechanism to achieve homeostasis during termination of an immune response. Activation of the activating protein-1 (AP-1) transcription factor and downregulation of Bcl-2 have been shown after exposure to gal-1.24 Gal-1-induced activation of the TCRz/Lck/ZAP70 pathway was proved to be essential to stimulate ceramide release and to trigger the mitochondrial pathway of apoptosis.[25]
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