A Serine/threonine Kinase, Cot/Tpl2, Modulates Bacterial DNA-induced IL-12 Production and Th Cell Differentiation

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2004 Sep 17

PMID 15372110

Citations 35

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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