Reference - Detail
|Author||Tsuji-Takayama K, Suzuki M, Yamamoto M, Harashima A, Okochi A, Otani T, Inoue T, Sugimoto A, Motoda R, Yamasaki F, Nakamura S, Kibata M.|
|Title||IL-2 activation of STAT5 enhances production of IL-10 from human cytotoxic regulatory T cells, HOZOT.|
OBJECTIVE:Interleukin (IL)-10 is an immunosuppressive cytokine produced by many cell types, including T cells. We previously reported that a novel type of regulatory T (Treg) cells, termed HOZOT, which possesses a FOXP3+CD4+CD8+CD25+ phenotype and dual suppressor/cytotoxic activities, produced high levels of IL-10. In this study, we examined the mechanisms of high IL-10 production by HOZOT, focusing on Janus activating kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway.
MATERIALS AND METHODS:We prepared five different types of T cells, including HOZOT from human umbilical cord blood. Cytokine productions of IL-10, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were compared among these T cells after anti-CD3/CD28 antibody stimulation in the presence or absence of IL-2. Specific inhibitors for JAK/STAT, nuclear factor-kappaB (NF-kappaB), and nuclear factor for activated T cell (NFAT) were used to analyze signal transduction mechanisms.
RESULTS:IL-10 production by HOZOTs was greatly enhanced by the addition of IL-2. Little or no enhancement of IFN-gamma and TNF-alpha production was observed under the same conditions. The enhancing effect of IL-2 was specific for both HOZOT and IL-10-secreting Treg cells. T helper type 2 cells, whose IL-10 production mechanisms involve GATA-3, failed to show IL-2-mediated enhancement of IL-10. Similar enhancing effects of IL-15 and IFN-alpha suggested a major role of JAK/STAT activation pathway for high IL-10 production. Further inhibitor experiments demonstrated that STAT5 rather than STAT3 was critically involved in this mechanism.
CONCLUSION:Our results demonstrated that IL-2 selectively enhanced production of IL-10 in HOZOT primarily through activation of STAT5, which synergistically acts with NF-kappaB/NFAT activation, implying a novel regulatory mechanism of IL-10 production in Treg cells.
|MeSH||Antibodies / immunology Antibodies / pharmacology Antigens, CD / immunology Antigens, CD / metabolism Cells, Cultured Humans Interferon-alpha / biosynthesis Interferon-alpha / immunology Interferon-gamma / biosynthesis Interferon-gamma / immunology Interleukin-10 / biosynthesis Interleukin-10 / immunology* Interleukin-15 / biosynthesis Interleukin-15 / immunology Interleukin-2 / immunology* Interleukin-2 / pharmacology Janus Kinases / immunology Janus Kinases / metabolism Lymphocyte Activation / drug effects Lymphocyte Activation / immunology* NFATC Transcription Factors / immunology NFATC Transcription Factors / metabolism STAT3 Transcription Factor / immunology STAT3 Transcription Factor / metabolism STAT5 Transcription Factor / immunology* STAT5 Transcription Factor / metabolism Signal Transduction / drug effects Signal Transduction / immunology T-Lymphocytes, Cytotoxic / cytology T-Lymphocytes, Cytotoxic / immunology* T-Lymphocytes, Cytotoxic / metabolism T-Lymphocytes, Regulatory / cytology T-Lymphocytes, Regulatory / immunology* T-Lymphocytes, Regulatory / metabolism Tumor Necrosis Factor-alpha / biosynthesis Tumor Necrosis Factor-alpha / immunology|
|WOS Category||MEDICINE, RESEARCH & EXPERIMENTAL HEMATOLOGY|
|Human and Animal Cells|