Positive modulation of IL-12 signaling by sphingosine kinase 2 associating with the IL-12 receptor beta 1 cytoplasmic region
| Autor: | Yasushi Magami, Junichiro Mizuguchi, Takayuki Yoshimoto, Koh Yamamoto, Hiromi Fujiwara, Hiroko Miyaji, Masayuki Hisada, Masae Furuhata, Sadahiro Kamiya |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Cytoplasm
T-Lymphocytes Mitogen-activated protein kinase kinase Lymphocyte Activation MAP2K7 GTP Phosphohydrolases Mice Tumor Cells Cultured Immunology and Allergy ASK1 Cells Cultured biology Receptors Interleukin-12 Nuclear Proteins STAT4 Transcription Factor Interleukin-12 Cell biology Up-Regulation DNA-Binding Proteins Isoenzymes Phosphotransferases (Alcohol Group Acceptor) Protein Binding Signal Transduction Gene Expression Regulation Viral Transcriptional Activation Immunology Molecular Sequence Data Down-Regulation Peptide Mapping Cell Line Interferon-gamma Two-Hybrid System Techniques Animals Humans Integrin-linked kinase Amino Acid Sequence Hybridomas MAP kinase kinase kinase Cyclin-dependent kinase 4 Cyclin-dependent kinase 2 Receptors Interleukin Th1 Cells Molecular biology Clone Cells Protein Structure Tertiary Mice Inbred C57BL Protein Subunits Retroviridae biology.protein Trans-Activators Cyclin-dependent kinase 9 |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 171(3) |
| ISSN: | 0022-1767 |
| Popis: | IL-12 is a key immunoregulatory cytokine that promotes Th1 differentiation and cell-mediated immune responses. IL-12 stimulation results in the activation of Janus kinase 2 and tyrosine kinase 2 and, subsequently, STAT4 and STAT3. In addition, mitogen-activated protein kinase kinase 6/p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways have been recently demonstrated to be activated by IL-12 and play an important role in IL-12 signaling. To further elucidate the molecular mechanism underlying IL-12 signaling, we have performed a yeast two-hybrid screening and identified mouse sphingosine kinase 2 (SPHK2) as a molecule associating with the mouse IL-12Rβ1 cytoplasmic region. Analyses of various mutants of each molecule revealed that the region including the proline-rich domain in SPHK2 is probably responsible for the binding to IL-12Rβ1, while the regions including the carboxyl terminus and Box II in the IL-12Rβ1 cytoplasmic region appear to be involved in the binding to SPHK2. Transient expression of wild-type SPHK2 in T cell hybridoma augmented IL-12-induced STAT4-mediated transcriptional activation. Ectopic expression of dominant-negative SPHK2 in Th1 cell clone significantly reduced IL-12-induced IFN-γ production, while that of wild-type SPHK2 enhanced it. In contrast, the expression minimally affected IL-12-induced proliferation. A similar decrease in IL-12-induced IFN-γ production was observed when dominant-negative SPHK2 was expressed in activated primary T cells using a retroviral expression system. These results suggest that SPHK2 associates with the IL-12Rβ1 cytoplasmic region and probably plays a role in modulating IL-12 signaling. |
| Databáze: | OpenAIRE |
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