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A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA–induced IL-12 production and Th cell differentiation
Kenji Sugimoto, … , Yasuhiro Shimada, Tetsuya Matsuguchi
Kenji Sugimoto, … , Yasuhiro Shimada, Tetsuya Matsuguchi
Published September 15, 2004
Citation Information: J Clin Invest. 2004;114(6):857-866. https://doi.org/10.1172/JCI20014.
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Article Immunology

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

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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.

Authors

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

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Figure 1

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Cot/Tpl2 activation by TLR ligands. (A) RAW 264.7 cells were stimulated ...
Cot/Tpl2 activation by TLR ligands. (A) RAW 264.7 cells were stimulated with 1 μg/ml LPS, 1 μg/ml synthetic lipopeptide, or 1 μM CpG-DNA for the indicated periods. In vitro kinase assays were performed with an Ab against Cot/Tpl2 and GST-MEK1 as the substrate. As a control, Western blot analyses were performed with Ab’s against Cot/Tpl2 and β-actin. sBLP, synthetic bacterial lipopeptide. (B) HEK 293 cells were transiently transfected with Flag-tagged Cot/Tpl2 in combination with either mouse TLR4 plus CD14 plus MD2 (mTLR4) or mouse TLR9 (mTLR9). Transfectants were stimulated for 30 minutes with 1 μg/ml LPS or 1 μM CpG-DNA, respectively. In vitro kinase assay was performed with anti-Flag Ab on GST-MEK1 as the substrate.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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