Suppressors of Cytokine Signaling Promote Fas-Induced Apoptosis through Downregulation of NF-κB and Mitochondrial Bfl-1 in Leukemic T Cells

Abstract

Suppressors of cytokine signaling (SOCS) are known as negative regulators of cytokine- and growth factor–induced signal transduction. Recently they have emerged as multifunctional proteins with regulatory roles in inflammation, autoimmunity, and cancer. We have recently reported that SOCS1 has antiapoptotic functions against the TNF-α– and the hydrogen peroxide–induced T cell apoptosis through the induction of thioredoxin, which protects protein tyrosine phosphatases and attenuates Jaks. In this study, we report that SOCS, on the contrary, promote death receptor Fas-mediated T cell apoptosis. The proapoptotic effect of SOCS1 was manifested with increases in Fas-induced caspase-8 activation, truncated Bid production, and mitochondrial dysfunctions. Both caspase-8 inhibitor c-Flip and mitochondrial antiapoptotic factor Bfl-1 were significantly reduced by SOCS1. These proapoptotic responses were not associated with changes in Jak or p38/Jnk activities but were accompanied with downregulation of NF-κB and NF-κB–dependent reporter gene expression. Indeed, p65 degradation via ubiquitination was accelerated in SOCS1 overexpressing cells, whereas it was attenuated in SOCS1 knockdown cells. With high NF-κB levels, the SOCS1-ablated cells displayed resistance against Fas-induced apoptosis, which was abrogated upon siBfl-1 transfection. The results indicate that the suppression of NF-κB–dependent induction of prosurvival factors, such as Bfl-1 and c-Flip, may serve as a mechanism for SOCS action to promote Fas-mediated T cell apoptosis. SOCS3 exhibited a similar proapoptotic function. Because both SOCS1 and SOCS3 are induced upon TCR stimulation, SOCS would play a role in activation-induced cell death by sensitizing activated T cells toward Fas-mediated apoptosis to maintain T cell homeostasis.

SOCS3 induces neurite differentiation and promotes neuronal cell survival

“…pAkt expression was also significantly upregulated in SOCS3 stables. Further it has been shown that SOCS1 has antiapoptotic properties and SOCS3 is important for the survival of prostate cancer cells (24,25). In our studies we observed that SOCS3 overexpression diminished the H 2 O 2 induced caspase-3 cleavage and enhanced expression of the prosurvival molecule Bcl2.…”

Growth inhibitory effect of β‐eudesmol on cholangiocarcinoma cells and its potential suppressive effect on heme oxygenase‐1 production, STAT1/3 activation, and NF‐κB downregulation

“…Since NF‐κB p50 is produced as a proteolytic product of the pre‐form NF‐κB1 (p105), for qualitative purpose, the inhibitory effect of β‐eudesomol on NF‐κB (p50) expression was considered as the representative measure of NF‐κB1/p50 downregulation. Similar studies involving chemostress‐induced downregulation of NF‐κB (p65) protein have previously been employed to access the inhibitory effects of various compounds on NF‐κB expression in leukemic T and hepatic cancer cells . Taken together, the inhibitory effect of β‐eudesmol on the production of cytoprotective enzymes and stimulatory effect on the expression of key transcriptional factor proteins may be linked to the observed cytotoxicity of the compound on CL‐6 cells.…”

Different Genetic Expression Profiles of Oxidative Stress and Apoptosis-Related Genes in Crohn’s Disease

“…Moreover, a downregulation of NFKB promotes Fas-induced apoptosis in T cells [36]. NFKB comprises a family of critical transcription factors involved in a variety of immunologic and/or inflammatory processes.…”