title: 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.
authors.affiliation: Laboratory of Immunology, Department of Biological Science, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Oh
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Sinae
authors.initials: S
authors.lastname: Ahn
authors.forename: Choong-Eun
authors.initials: CE
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology*; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology; D045325:HCT116 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D015778:Minor Histocompatibility Antigens; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000502:physiology*
chemical_list: C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019014:fas Receptor