A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation

Kenji Sugimoto, Mutsuhiro Ohata, Jun Miyoshi, Hiroyoshi Ishizaki, Naotake Tsuboi, Akio Masuda, Yasunobu Yoshikai, Masaya Takamoto, Kazuo Sugane, Seiichi Matsuo, Yasuhiro Shimada, Tetsuya Matsuguchi

    Research output: Contribution to journalArticle

    66 Citations (Scopus)

    Abstract

    A serine/threonine protein kinase, Cot/Tpl2, is indispensable for extracellular signal-regulated kinase (ERK) activation and production of TNF-α 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.

    Original languageEnglish
    Pages (from-to)857-866
    Number of pages10
    JournalJournal of Clinical Investigation
    Volume114
    Issue number6
    DOIs
    Publication statusPublished - Jan 1 2004

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    Bacterial DNA
    Protein-Serine-Threonine Kinases
    Interleukin-12
    Cell Differentiation
    Macrophages
    Extracellular Signal-Regulated MAP Kinases
    DNA
    GA-Binding Protein Transcription Factor
    Lipopeptides
    Leishmania major
    Fibrosarcoma
    Toll-Like Receptors
    Histocompatibility Antigens Class II
    Peritoneal Macrophages
    Adaptive Immunity
    Dinoprostone
    Immunization
    Carrier Proteins
    Vaccination
    Bone Marrow

    All Science Journal Classification (ASJC) codes

    • Medicine(all)

    Cite this

    Sugimoto, K., Ohata, M., Miyoshi, J., Ishizaki, H., Tsuboi, N., Masuda, A., ... Matsuguchi, T. (2004). A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. Journal of Clinical Investigation, 114(6), 857-866. https://doi.org/10.1172/JCI20014

    A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. / Sugimoto, Kenji; Ohata, Mutsuhiro; Miyoshi, Jun; Ishizaki, Hiroyoshi; Tsuboi, Naotake; Masuda, Akio; Yoshikai, Yasunobu; Takamoto, Masaya; Sugane, Kazuo; Matsuo, Seiichi; Shimada, Yasuhiro; Matsuguchi, Tetsuya.

    In: Journal of Clinical Investigation, Vol. 114, No. 6, 01.01.2004, p. 857-866.

    Research output: Contribution to journalArticle

    Sugimoto, K, Ohata, M, Miyoshi, J, Ishizaki, H, Tsuboi, N, Masuda, A, Yoshikai, Y, Takamoto, M, Sugane, K, Matsuo, S, Shimada, Y & Matsuguchi, T 2004, 'A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation', Journal of Clinical Investigation, vol. 114, no. 6, pp. 857-866. https://doi.org/10.1172/JCI20014
    Sugimoto, Kenji ; Ohata, Mutsuhiro ; Miyoshi, Jun ; Ishizaki, Hiroyoshi ; Tsuboi, Naotake ; Masuda, Akio ; Yoshikai, Yasunobu ; Takamoto, Masaya ; Sugane, Kazuo ; Matsuo, Seiichi ; Shimada, Yasuhiro ; Matsuguchi, Tetsuya. / A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 6. pp. 857-866.
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    AU - Miyoshi, Jun

    AU - Ishizaki, Hiroyoshi

    AU - Tsuboi, Naotake

    AU - Masuda, Akio

    AU - Yoshikai, Yasunobu

    AU - Takamoto, Masaya

    AU - Sugane, Kazuo

    AU - Matsuo, Seiichi

    AU - Shimada, Yasuhiro

    AU - Matsuguchi, Tetsuya

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