A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA–induced IL-12 production and Th cell differentiation
| Autor: | Hiroyoshi Ishizaki, Seiichi Matsuo, Jun Miyoshi, Kazuo Sugane, Tetsuya Matsuguchi, Naotake Tsuboi, Masaya Takamoto, Yasunobu Yoshikai, Yasuhiro Shimada, Akio Masuda, Mutsuhiro Ohata, Kenji Sugimoto |
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| Rok vydání: | 2004 |
| Předmět: |
DNA
Bacterial MAPK/ERK pathway Molecular Sequence Data Cell Culture Techniques Biology Polymerase Chain Reaction Article Mice Proto-Oncogene Proteins Animals Threonine Protein kinase A Receptor DNA Primers Mice Knockout Serine/threonine-specific protein kinase Base Sequence MAP kinase kinase kinase Kinase Exons General Medicine Th1 Cells MAP Kinase Kinase Kinases Interleukin-12 Molecular biology Macrophages Peritoneal Interleukin 12 |
| Zdroj: | Journal of Clinical Investigation. 114:857-866 |
| ISSN: | 0021-9738 |
| Popis: | A serine/threonine protein kinase, Cot/Tpl2, is indispensable for extracellular signal-regulated kinase (ERK) activation and production of TNF-alpha and PGE2 in LPS-stimulated macrophages. We show here that Cot/Tpl2 is also activated by other Toll-like receptor (TLR) ligands. Bacterial DNA rich in the dinucleotide CG (CpG-DNA), unlike LPS or synthetic lipopeptide, activated ERK in a Cot/Tpl2-independent manner. Peritoneal macrophages and bone marrow-derived DCs from Cot/Tpl2-/- mice produced significantly more IL-12 in response to CpG-DNA than those from WT mice. Enhanced IL-12 production in Cot/Tpl2-/- macrophages is, at least partly, regulated at the transcriptional level, and the elevated IL-12 mRNA level in Cot/Tpl2-/- macrophages is accompanied by decreased amounts of IL-12 repressors, such as c-musculoaponeurotic fibrosarcoma (c-Maf) and GATA sequence in the IL-12 promoter-binding protein (GA-12-binding protein; GAP-12) in the nucleus. Consistently, Cot/Tpl2-/- mice showed Th1-skewed antigen-specific immune responses upon OVA immunization and Leishmania major infection in vivo. These results indicate that Cot/Tpl2 is an important negative regulator of Th1-type adaptive immunity, that it achieves this regulation by inhibiting IL-12 production from accessory cells, and that it might be a potential target molecule in CpG-DNA-guided vaccination. |
| Databáze: | OpenAIRE |
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